{"gene":"KCNA1","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":1994,"finding":"KCNA1 (Kv1.1) missense point mutations in heterozygous state cause episodic ataxia/myokymia syndrome, establishing KCNA1 as the disease gene for EA1","method":"Mutation analysis of KCNA1 coding region in EA1 families; heterologous expression","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — foundational genetic + functional study, replicated across multiple families and labs","pmids":["7842011"],"is_preprint":false},{"year":1994,"finding":"Kv1.1 protein localizes to synaptic terminals, juxta-paranodal regions of myelinated axons, unmyelinated axons, cell somata, and proximal dendrites in mouse brain","method":"Immunocytochemistry/immunohistochemistry with isoform-specific antisera in mouse brain","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — direct localization with isoform-specific antibodies, highly cited foundational study","pmids":["8046438"],"is_preprint":false},{"year":1994,"finding":"Kv1.1 assembles cotranslationally with other Shaker-like subunits (e.g., Kv1.4) but not with non-Shaker subunits (Kv2.1); N207 glycosylation occurs but is not required for assembly, transport, or function; channel appears as 57–59 kDa doublet reflecting posttranslational processing","method":"Co-immunoprecipitation from in vitro translations and transfected cells; pulse-chase metabolic labeling; site-directed mutagenesis of glycosylation site; electrophysiology","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with co-IP and mutagenesis in a single rigorous study","pmids":["8126562"],"is_preprint":false},{"year":1995,"finding":"Ca2+-independent phospholipase A2 modulates Kv1.1 channel kinetics through release of arachidonic acid, which accelerates both activation and induces inactivation of Kv1.1 currents","method":"Intracellular administration of PLA2 and exogenous arachidonic acid in Sf9 cells expressing Kv1.1; whole-cell patch clamp; mechanism-based PLA2 inhibitor controls","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with enzymatic and chemical controls, multiple orthogonal approaches","pmids":["7852365"],"is_preprint":false},{"year":1996,"finding":"Sialic acid addition to Kv1.1 modulates voltage dependence of activation by influencing the local electric field at the voltage sensor; sialidase treatment or elevated Ca2+ shifts activation to more positive voltages, mimicking effects seen in glycosylation-deficient cell lines","method":"Expression in Lec mutant CHO cells deficient in glycosylation; sialidase treatment; whole-cell patch clamp","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstitution in glycosylation mutant lines with pharmacological validation","pmids":["8702582"],"is_preprint":false},{"year":1998,"finding":"EA1 mutations in Kv1.1 impair channel function by two distinct mechanisms: dominant negative effects (most mutations form heteromeric channels with intermediate properties) or haploinsufficiency (R239S and F249I yield minimal protein and current)","method":"Heterologous expression in Xenopus oocytes; TEA-tagging to distinguish subunit contributions; Western blot for protein levels","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis with pharmacological subunit discrimination and protein quantification","pmids":["9526001"],"is_preprint":false},{"year":1998,"finding":"Kv1.1 knockout mice exhibit hyperalgesia (reduced nociceptive thresholds in paw flick, hot plate, and formalin assays) and blunted morphine antinociception, establishing Kv1.1 as a regulator of nociceptive and antinociceptive signaling","method":"Behavioral pain assays in Kcna1-null mice (-/-) versus heterozygous (+/-) and wild-type (+/+) littermates","journal":"Neuroscience letters","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined behavioral phenotype across multiple pain assays","pmids":["9718989"],"is_preprint":false},{"year":1998,"finding":"Kv1.1 mRNA is destabilized by cAMP elevation in C6 glioma cells, reducing Kv1.1 protein and outward K+ current, and thereby depolarizing resting membrane potential","method":"cAMP elevation by pharmacological agents; Northern blot for RNA decay; Western blot; whole-cell patch clamp; dendrotoxin-I pharmacology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods in single lab, functional consequence demonstrated","pmids":["9636212"],"is_preprint":false},{"year":1999,"finding":"EA1 mutations V408A and E325D in Kv1.1 co-assemble with Kv1.2 to form heteromeric channels with altered kinetics of activation, deactivation, C-type inactivation, and voltage dependence; V408A reduces mean single-channel open duration ~3-fold","method":"Tandemly linked subunits expressed in Xenopus oocytes; single-channel and macroscopic patch clamp analysis","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 — tandem-linked subunit constructs with single-channel analysis providing mechanistic detail","pmids":["10428758"],"is_preprint":false},{"year":1999,"finding":"Protein kinase C activation inhibits Kv1.1 current by a mechanism requiring a C3 exoenzyme substrate (Rho GTPase pathway) but does not alter channel gating kinetics or promote channel internalization; inhibition is not via direct phosphorylation of Kv1.1","method":"PMA application in Xenopus oocytes; PKC inhibitors; site-directed mutagenesis of PKC sites; Western blot; botulinum toxin C3 injection","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis plus pharmacological dissection in single lab","pmids":["10409113"],"is_preprint":false},{"year":2000,"finding":"Four EA1 KCNA1 mutations impair delayed-rectifier K+ currents by different mechanisms: some alter gating properties, others cause truncation with dominant negative effects; phenotypic variability correlates with degree and nature of channel dysfunction","method":"Heterologous expression in Xenopus oocytes; electrophysiology; confocal microscopy of GFP-tagged subunits","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple mutations characterized with electrophysiology and imaging","pmids":["11026449"],"is_preprint":false},{"year":2001,"finding":"EA1 missense mutations generate Kv1.1 subunits with normal folding and trafficking, whereas the nonsense truncation mutation causes intracellular aggregation and detergent insolubility that can be transferred to co-assembled Kv1 α- and Kvβ-subunits","method":"Immunocytochemistry; detergent solubility assays; co-assembly studies in heterologous cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical methods in single lab demonstrating distinct trafficking phenotypes","pmids":["11679591"],"is_preprint":false},{"year":2002,"finding":"EA1 mutation R417stop (C-terminal truncation) impairs both tetramerization of Kv1.1 with wild-type subunits and membrane targeting of heterotetramers, while typical EA1 mutations (e.g., V404I, P244H) affect only channel kinetics without disrupting assembly or trafficking","method":"Co-expression in Xenopus oocytes; pharmacological discrimination of subunit contribution; confocal imaging of GFP-tagged subunits","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple complementary approaches with pharmacological subunit tagging and imaging","pmids":["11773313"],"is_preprint":false},{"year":2002,"finding":"EA1 mutations E325D and V408A destabilize the open state of Kv1.1, increasing deactivation rates ~10-fold, and alter Kvβ1-induced N-type inactivation: inactivation onset is ~2-fold slower and recovery is ~10-fold faster than wild-type","method":"Heterologous expression with Kvβ1 in Xenopus oocytes; macroscopic and gating current recording; comparison of homomeric and heteromeric channels","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 — rigorous electrophysiological characterization with systematic stoichiometry controls","pmids":["12077175"],"is_preprint":false},{"year":2003,"finding":"Kv1.1 subunits contribute approximately half the low-threshold IKL current in auditory MNTB neurons; absence of Kv1.1 (Kcna1-null) reduces IKL amplitude by ~50% and doubles neuronal excitability (more APs, halved threshold current); residual IKL is DTX-sensitive, suggesting Kv1.2/Kv1.6 compensation","method":"Whole-cell patch clamp in brainstem slices from Kcna1-null and wild-type mice; DTX pharmacology","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with quantitative electrophysiology and pharmacological dissection","pmids":["12611922"],"is_preprint":false},{"year":2003,"finding":"Glycosylation at the S1-S2 linker affects Kv1.1 gating function but, unlike Kv1.4, does not influence protein stability or cell-surface expression; a pore-region determinant dictates differential glycosylation effects on trafficking between Kv1.1 and Kv1.4","method":"N-glycosylation mutants; cell-surface biotinylation; immunocytochemistry; electrophysiology in transfected cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — chimeric channel strategy with mutagenesis identifies pore-region determinant","pmids":["14688283"],"is_preprint":false},{"year":2003,"finding":"KCNA1 11-bp deletion (mceph mouse) produces a truncated Kv1.1 that retains only N-terminal assembly domains, sequesters Kv1.2 and Kv1.3 subunits, reduces their protein levels in hippocampus, and causes seizures and megalencephaly","method":"Positional cloning; immunoblot for Kv1.2 and Kv1.3; immunohistochemistry; EEG","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — genetic model with protein biochemistry demonstrating dominant-negative sequestration","pmids":["14686897"],"is_preprint":false},{"year":2005,"finding":"Human Kv1.1 is palmitoylated at C243 in the S2-S3 cytosolic linker; preventing palmitoylation at C243 causes a 20-mV leftward shift in the current-voltage relationship, indicating palmitoylation modulates voltage sensing","method":"[3H]palmitate radiolabeling; chemical stability studies; site-directed mutagenesis; whole-cell patch clamp in Sf9 cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with radiolabeling, mutagenesis, and functional electrophysiology","pmids":["15837928"],"is_preprint":false},{"year":2003,"finding":"Absence of Kv1.1 in Kcna1-null mice reduces temporal precision of auditory signaling: increased first-spike latency jitter in VCN bushy cells, calyceal terminals, and MNTB neurons in vivo, and reduced ability to follow high-frequency amplitude-modulated stimulation","method":"In vivo single-unit recordings from VCN and MNTB neurons in Kcna1-null vs. wild-type mice","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — clean KO with in vivo electrophysiology across multiple auditory stations","pmids":["14534254"],"is_preprint":false},{"year":2006,"finding":"mTOR activity suppresses Kv1.1 mRNA translation in dendrites; inhibition of mTOR (rapamycin) or NMDA receptors increases dendritic Kv1.1 protein and surface expression without altering axonal expression; endogenous Kv1.1 mRNA is present in dendrites","method":"Live imaging of Kaede-Kv1.1 reporter for local synthesis; rapamycin treatment; surface biotinylation; immunostaining in hippocampal neurons","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 — photoconvertible reporter for local synthesis plus pharmacological dissection, multiple orthogonal methods","pmids":["17023663"],"is_preprint":false},{"year":2006,"finding":"Kv1.1-containing channels (identified by DTX-K) underlie IKL in MNTB neurons and are critical for temporal precision of action potential initiation; pharmacological or genetic reduction of Kv1.1 increases AP latency jitter, particularly during rapid stimulation (100-500 Hz)","method":"Pharmacology with DTX-K at selective concentrations; whole-cell patch clamp in Kcna1-/- mouse brain slices; comparison of genetic and pharmacological IKL reduction","journal":"Journal of neurophysiology","confidence":"High","confidence_rationale":"Tier 2 — parallel pharmacological and genetic approaches yield concordant results","pmids":["16672305"],"is_preprint":false},{"year":2006,"finding":"EA1 mutations E325D, V404I, V408A, and I177N alter N-type inactivation and repriming properties of heteromeric Kv1.4-Kv1.1/Kvβ1.1 and Kv1.4-Kv1.1/Kvβ1.2 channels, decreasing inactivation rate and accelerating recovery from inactivation","method":"Tandemly linked subunits in Xenopus oocytes; two-electrode voltage clamp","journal":"The European journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 — tandem-linked constructs isolating subunit contributions with systematic mutation analysis","pmids":["17156368"],"is_preprint":false},{"year":2003,"finding":"PKA activation phosphorylates intracellular Kv1.1 protein and promotes its rapid translocation to the plasma membrane, increasing current amplitude and altering voltage dependence of activation; PKC activation does not directly phosphorylate Kv1.1 but induces Kv1.1 protein synthesis","method":"Patch clamp in stably transfected HEK293 cells; PKA/PKC activators; phosphorylation assays","journal":"Neuropharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods in single lab demonstrating PKA-dependent translocation and functional change","pmids":["12681381"],"is_preprint":false},{"year":2008,"finding":"Kvβ1 is a functional aldoketoreductase; oxidation of Kvβ1-bound NADPH cofactor (enzymatically or by H2O2/NADP+) induces a large increase in Kv1.1 open-channel current; the rate of cofactor oxidation is regulated by membrane potential (~2-fold faster at 0 mV vs. -100 mV), linking metabolic state to channel function","method":"In vitro aldoketoreductase assay for Kvβ1; electrophysiology with NADP+/H2O2 application; site-directed mutagenesis of catalytic site; whole-cell patch clamp","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — enzymatic reconstitution combined with electrophysiology and mutagenesis","pmids":["18222921"],"is_preprint":false},{"year":2009,"finding":"A KCNA1 N255D mutation causes autosomal dominant hypomagnesemia; Kv1.1 is expressed in the distal convoluted tubule where it colocalizes with TRPM6 at the luminal membrane, and N255D produces a non-functional channel with dominant negative effect on wild-type Kv1.1, disrupting the membrane potential needed for TRPM6-mediated Mg2+ reabsorption","method":"Positional cloning; immunolocalization in kidney; patch clamp in human kidney cell line; overexpression studies","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 — positional cloning plus patch clamp and colocalization providing pathway mechanism","pmids":["19307729"],"is_preprint":false},{"year":2009,"finding":"Asparagine at position 255 in the S3 transmembrane segment of Kv1.1 is essential for normal voltage dependence and gating kinetics; charged or bulky substitutions (N255D, N255E, N255Q) abolish ion conduction while other substitutions shift activation to more negative potentials and alter kinetics","method":"Systematic mutagenesis at N255; cell surface biotinylation; whole-cell patch clamp in HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis with electrophysiology characterizing structure-function at a specific residue","pmids":["19903818"],"is_preprint":false},{"year":2010,"finding":"Kv1.1 deficiency (Kcna1-null) causes brain-driven cardiac dysfunction including AV conduction blocks, bradycardia, and premature ventricular contractions; these arise from excessive parasympathetic tone (reversed by atropine but not propranolol); Kv1.1 is expressed in juxtaparanodes of the vagus nerve, suggesting it regulates parasympathetic outflow to the heart","method":"Simultaneous video EEG-ECG recordings; selective autonomic pharmacological blockade (atropine/propranolol); immunohistochemistry of vagus nerve; cardiac structural analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — KO model with pharmacological dissection of autonomic mechanism and localization evidence","pmids":["20392939"],"is_preprint":false},{"year":2011,"finding":"NRG1 acting through ErbB4 increases intrinsic excitability of fast-spiking parvalbumin interneurons by increasing near-threshold responsiveness and decreasing action potential voltage threshold through Kv1.1","method":"Whole-cell patch clamp in ErbB4 conditional knockout mice; pharmacological manipulation of Kv1.1; seizure susceptibility models","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 — genetic and pharmacological dissection with defined cellular and behavioral readouts","pmids":["22158511"],"is_preprint":false},{"year":2013,"finding":"mTOR-dependent regulation of Kv1.1 mRNA translation in dendrites involves two opposing mechanisms: when mTORC1 is active, miR-129 represses Kv1.1 mRNA translation; when mTORC1 is inhibited, degradation of high-affinity HuD target mRNAs frees HuD to bind and promote Kv1.1 mRNA translation","method":"miRNA identification; HuD RNA-binding protein binding assays; mTOR inhibition studies; polysome profiling; reporter assays in neurons","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — mechanistic dissection of competing translational regulators with multiple orthogonal methods","pmids":["23836929"],"is_preprint":false},{"year":2013,"finding":"Kv1.1 acts as a mechanosensitive brake in sensory neurons: mechanosensitivity is attributed to Kv1.1 subunits in Kv1.1-Kv1.2 heteromers through facilitation of voltage-dependent open probability; IKmech expression in C-HTMRs opposes slow MS cation currents, setting mechanical firing threshold; Kv1.1 dominant negative or inhibition causes mechanical allodynia without heat hyperalgesia","method":"Toxin profiling; transgenic mouse studies; patch clamp of DRG neurons; Kv1.1 dominant negative expression; behavioral assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — convergent genetic and pharmacological evidence with behavioral phenotype","pmids":["23473320"],"is_preprint":false},{"year":2013,"finding":"Loss of Kv1.1 in Kcna1-null hippocampus increases presynaptic neurotransmitter release at mossy fiber and perforant path terminals (reduced paired-pulse ratios, enhanced postsynaptic responses), which reduces spike timing reliability of CA3 principal cells and promotes pathological high-frequency oscillations","method":"Multielectrode array extracellular recordings; micro-dissection experiments; DTX-κ pharmacology in wild-type slices","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 — KO model with pharmacological validation and circuit dissection","pmids":["23466697"],"is_preprint":false},{"year":2013,"finding":"KCNA1 expression is induced by oncogenic stress, and Kv1.1 relocates from cytoplasm to plasma membrane upon loss of PKA-dependent phosphorylation at S446; membrane-localized Kv1.1 changes membrane potential and triggers cellular senescence; phosphomimetic S446 mutant maintains cytoplasmic localization and allows OIS escape","method":"Loss-of-function genetic screen; subcellular fractionation; mutagenesis of S446; membrane potential measurements; transformation assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — genetic screen validated with mutagenesis and functional assays in single lab","pmids":["23774215"],"is_preprint":false},{"year":2003,"finding":"KCNE4 β-subunit exerts a drastic inhibitory effect specifically on Kv1.1 and Kv1.3 homomeric currents and on Kv1.1/Kv1.2 and Kv1.2/Kv1.3 heteromeric currents but not on Kv1.2, Kv1.4, Kv1.5, or Kv4.3; Kv1.1 and KCNE4 colocalize at the cell surface","method":"Heterologous expression in Xenopus oocytes and HEK293 cells; electrophysiology; confocal microscopy; Western blot","journal":"Biophysical journal","confidence":"High","confidence_rationale":"Tier 2 — systematic channel specificity testing in two expression systems with localization","pmids":["12944270"],"is_preprint":false},{"year":2011,"finding":"Kv1.1 (V408A/+) knock-in mice exhibit spontaneous myokymic discharges originating from motor nerve axons independent of neuromuscular junction; the V408A mutation causes abnormal spontaneous Ca2+ signals in motor nerve axons; fatigue, ischemia, and low temperature exacerbate myokymic activity","method":"In vivo nerve-muscle preparations; two-photon laser scanning microscopy of Ca2+ signals; nerve axotomy experiments; EMG recordings","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 — knock-in mouse model with two-photon imaging and axotomy dissecting site of origin","pmids":["22609489"],"is_preprint":false},{"year":2014,"finding":"Following kainic-acid induced status epilepticus, Kv1.1 expression is suppressed in two phases: (1) initial mTOR-dependent suppression (reversed by rapamycin) followed by (2) persistent miR-129-5p-mediated translational repression independent of mTOR; reduced Kv1.1 in CA1 pyramidal neurons lowers action potential firing threshold","method":"Kainic acid TLE model; rapamycin treatment; miR-129-5p quantification; patch clamp recordings from CA1 neurons","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 — two distinct mechanistic phases identified with pharmacology, miRNA measurements, and electrophysiology","pmids":["25270294"],"is_preprint":false},{"year":2017,"finding":"Pharmacological or genetic deletion of Kv1.1 broadens presynaptic spike width; an EA1 heterozygous dominant Kv1.1 mutation (V408A) similarly broadens basal presynaptic spike shape but, unlike deletion, abolishes spike width modulation by subthreshold somatic depolarization, suggesting disruption of normal presynaptic Kv1 channel stoichiometry","method":"Scanning ion conductance microscopy to record from intact small synaptic boutons; pharmacological Kv1.1 blockade; heterozygous Kv1.1 V408A knock-in mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — novel recording method from intact boutons with parallel pharmacological and genetic approaches","pmids":["28193892"],"is_preprint":false},{"year":2018,"finding":"Patient-derived LGI1 antibodies disrupt LGI1 interaction with ADAM23 (presynaptic) and ADAM22 (postsynaptic), causing decreased synaptic Kv1.1 levels before AMPA receptor reduction, leading to neuronal hyperexcitability, increased presynaptic glutamate release, and impaired LTP","method":"Patient IgG cerebroventricular transfer in mice; confocal analysis of hippocampal slices; patch clamp of dentate gyrus and CA1 neurons; field potential LTP recordings","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 — patient antibody model with electrophysiology showing Kv1.1 reduction precedes AMPA receptor loss","pmids":["30346486"],"is_preprint":false},{"year":2020,"finding":"Neuron-specific deletion of Kcna1 (using Synapsin1-Cre) is sufficient to cause epilepsy, premature death, and cardiorespiratory dysregulation, demonstrating that brain-driven (not cardiac-intrinsic) Kv1.1 deficiency underlies SUDEP risk; residual Kv1.1 in cerebellum (where Synapsin1-Cre is less active) may modulate ictal cardiorespiratory dysfunction","method":"Conditional knockout (floxed Kcna1 × Synapsin1-Cre); EEG, ECG, plethysmography; survival analysis; heart rate variability analysis","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with multimodal physiological recording establishing neuron-specific mechanism","pmids":["31978607"],"is_preprint":false},{"year":2011,"finding":"RNA editing of Kv1.1 at position I400V (Ile→Val) in the S6 segment generates 4-aminopyridine-insensitive channels; editing ratio is increased ~4-fold in the entorhinal cortex of chronic epileptic rats, reducing ictogenic potential of 4-AP","method":"Sequencing of RNA editing in kainic acid model; electrophysiology of I400V channels in Xenopus oocytes","journal":"Epilepsia","confidence":"Medium","confidence_rationale":"Tier 2 — functional validation of editing site in oocytes correlated with in vivo editing measurements","pmids":["21371023"],"is_preprint":false},{"year":2018,"finding":"KCNA1 L319R mutation accelerates protein degradation via the proteasome pathway and disrupts Kv1.1 membrane expression; both L319R and N255K mutations reduce K+ currents with altered gating and dominant negative effect, causing familial paroxysmal kinesigenic dyskinesia","method":"Whole-exome sequencing; proteasome inhibitor experiments; patch clamp in HEK293 cells; dominant-negative co-expression","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical degradation assay plus electrophysiology in single lab","pmids":["29294000"],"is_preprint":false},{"year":2005,"finding":"Kv1.1 deletion augments carotid body chemosensory discharge during hypoxia and increases frequency of spontaneous and miniature EPSCs in nucleus tractus solitarius neurons, demonstrating Kv1.1 regulates afferent hypoxic chemosensory pathway and respiratory control","method":"Plethysmography; in vitro carotid body sensory discharge recordings; whole-cell patch clamp of NTS neurons in brainstem slices; immunohistochemistry","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — KO model with in vitro and in vivo recordings across multiple levels of chemosensory pathway","pmids":["15800194"],"is_preprint":false},{"year":2007,"finding":"Mu opioid receptor activation inhibits GABAergic inputs to basolateral amygdala neurons through presynaptic Kv1.1/1.2 channels; selective Kv1.1 blocker (DTX-K) abolishes DAMGO's inhibitory effect on mIPSCs; Kv1.1 and Kv1.2 colocalize with synaptophysin in BLA","method":"Whole-cell voltage clamp with selective toxin blockers (DTX-K for Kv1.1, tityustoxin-Kα for Kv1.2); double immunofluorescence with synaptophysin","journal":"Journal of neurophysiology","confidence":"Medium","confidence_rationale":"Tier 3 — pharmacological specificity supported by colocalization; single lab","pmids":["16306173"],"is_preprint":false},{"year":2007,"finding":"Nitric oxide increases GABAergic mIPSC frequency to PVN presympathetic neurons through cGMP/PKG signaling acting downstream on presynaptic Kv1.1/1.2 channels; selective blockade of Kv1.1 (DTX-K) or Kv1.2 abolishes NO-induced potentiation of GABA release","method":"Whole-cell patch clamp in PVN brain slices; selective Kv channel blockers; 8-Br-cADPR controls; immunofluorescence for Kv1.1/Kv1.2 and synaptophysin","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2-3 — pharmacological pathway placement with colocalization; single lab","pmids":["17869444"],"is_preprint":false},{"year":2010,"finding":"Kv1.1 and Kv1.3 channels contribute to RGC degeneration after optic nerve transection through different apoptotic pathways: Kv1.1 siRNA knockdown increases antiapoptotic Bcl-XL, while Kv1.3 siRNA reduces proapoptotic caspase-3, caspase-9, and Bad","method":"siRNA knockdown via intraocular injection with retrograde transport to RGCs; quantitative RT-PCR; immunohistochemistry; cell death counting","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — channel-specific siRNAs with defined apoptotic marker readouts","pmids":["19696788"],"is_preprint":false}],"current_model":"KCNA1-encoded Kv1.1 is a voltage-gated delayed-rectifier K+ channel subunit that forms homo- and heterotetramers (with Kv1.2, Kv1.4, Kv1.6, and Kvβ subunits) targeted to axonal juxtaparanodes, presynaptic terminals, and dendrites, where it dampens neuronal excitability by setting action potential threshold, controlling firing precision and spike width; its activity is regulated by palmitoylation at C243 (voltage sensing), PKA-driven phosphorylation and membrane translocation, arachidonic acid via Ca2+-independent PLA2, mTOR- and miR-129-dependent translational control of dendritic mRNA, and Kvβ1 aldoketoreductase-dependent cofactor oxidation; loss-of-function mutations or deficiency cause episodic ataxia type 1, seizures, myokymia, hypomagnesemia, and SUDEP through enhanced neuronal excitability and, in the brain, aberrant parasympathetic outflow to the heart."},"narrative":{"teleology":[{"year":1994,"claim":"Establishing that KCNA1 is the disease gene for episodic ataxia type 1 linked loss-of-function K⁺ channel mutations to a defined human neurological disorder.","evidence":"Mutation analysis of KCNA1 coding region across EA1 families with heterologous expression confirming functional deficits","pmids":["7842011"],"confidence":"High","gaps":["Precise mechanism of dominant-negative vs. haploinsufficiency for each mutation not yet resolved","No structural model explaining mutation-specific gating defects"]},{"year":1994,"claim":"Mapping Kv1.1 protein to synaptic terminals, juxtaparanodes, and dendrites defined the subcellular compartments where the channel regulates excitability.","evidence":"Isoform-specific immunocytochemistry in mouse brain","pmids":["8046438"],"confidence":"High","gaps":["Relative contribution of each subcellular pool to specific physiological functions not determined"]},{"year":1994,"claim":"Demonstrating cotranslational assembly of Kv1.1 exclusively with other Shaker-family subunits established the rules governing channel heteromerization.","evidence":"Co-immunoprecipitation from in vitro translations and transfected cells; pulse-chase metabolic labeling; glycosylation site mutagenesis","pmids":["8126562"],"confidence":"High","gaps":["Stoichiometry of heteromeric complexes in native tissue not determined","Assembly chaperone requirements unknown"]},{"year":1995,"claim":"Identifying arachidonic acid released by Ca²⁺-independent PLA2 as a modulator of Kv1.1 gating kinetics revealed a lipid-signaling regulatory axis.","evidence":"Intracellular PLA2 and exogenous arachidonic acid application with mechanism-based inhibitors; whole-cell patch clamp in Sf9 cells","pmids":["7852365"],"confidence":"High","gaps":["Direct binding site on Kv1.1 for arachidonic acid not identified","In vivo relevance not established"]},{"year":1996,"claim":"Showing that sialic acid glycosylation modulates voltage dependence of activation by altering the local electric field linked post-translational glycan processing to channel biophysics.","evidence":"Expression in glycosylation-deficient CHO Lec mutant cells; sialidase treatment; electrophysiology","pmids":["8702582"],"confidence":"High","gaps":["In vivo glycosylation heterogeneity at Kv1.1 not characterized"]},{"year":1998,"claim":"Systematic analysis of EA1 mutations separated two mechanistic classes—dominant-negative effects on heteromeric channels versus haploinsufficiency from protein instability—explaining clinical variability.","evidence":"TEA-tagging strategy in Xenopus oocytes to discriminate subunit contributions; Western blot quantification","pmids":["9526001"],"confidence":"High","gaps":["Genotype-phenotype correlation across all known EA1 mutations incomplete"]},{"year":1998,"claim":"Kcna1-null mice revealed Kv1.1 as a regulator of pain processing, with knockout causing hyperalgesia and blunted morphine antinociception.","evidence":"Behavioral pain assays (paw flick, hot plate, formalin) in Kcna1-null vs. wild-type mice","pmids":["9718989"],"confidence":"High","gaps":["Specific DRG neuron subtypes mediating Kv1.1-dependent nociception not identified at this time"]},{"year":2003,"claim":"Quantitative electrophysiology in Kcna1-null brainstem slices and in vivo recordings established that Kv1.1 supplies ~50% of low-threshold K⁺ current in auditory neurons and is essential for temporal precision of spike initiation.","evidence":"Patch clamp in MNTB slices from Kcna1-null mice; DTX pharmacology; in vivo single-unit recordings from VCN and MNTB","pmids":["12611922","14534254"],"confidence":"High","gaps":["Identity of compensatory Kv1.2/Kv1.6 contribution quantified only indirectly via DTX sensitivity"]},{"year":2003,"claim":"PKA phosphorylation was shown to drive rapid Kv1.1 translocation to the plasma membrane, increasing current and altering voltage dependence, while PKC acted indirectly through protein synthesis.","evidence":"Patch clamp in stably transfected HEK293 cells with PKA/PKC activators; phosphorylation assays","pmids":["12681381"],"confidence":"Medium","gaps":["Specific PKA phosphorylation site(s) not mapped in this study","In vivo confirmation of PKA-dependent trafficking lacking"]},{"year":2003,"claim":"The mceph mouse truncation and KCNE4 β-subunit studies revealed additional mechanisms of Kv1.1 suppression—dominant-negative sequestration of partner subunits and β-subunit-mediated current inhibition, respectively.","evidence":"Positional cloning with immunoblot showing reduced Kv1.2/Kv1.3 in mceph hippocampus; heterologous KCNE4 co-expression in oocytes and HEK293 cells","pmids":["14686897","12944270"],"confidence":"High","gaps":["KCNE4-Kv1.1 stoichiometry and binding interface unknown"]},{"year":2005,"claim":"Identifying palmitoylation at C243 as a modulator of voltage sensing (20 mV shift in I-V curve) linked a reversible lipid modification to the biophysics of Kv1.1 gating.","evidence":"[³H]palmitate radiolabeling; C243 mutagenesis; whole-cell patch clamp in Sf9 cells","pmids":["15837928"],"confidence":"High","gaps":["Palmitoyl acyltransferase responsible not identified","Dynamic regulation of palmitoylation state in neurons not characterized"]},{"year":2005,"claim":"Kv1.1 was placed in the afferent hypoxic chemosensory pathway: its deletion augmented carotid body discharge and excitatory transmission in NTS, linking Kv1.1 to respiratory control.","evidence":"Plethysmography; in vitro carotid body recordings; patch clamp of NTS neurons in Kcna1-null mice","pmids":["15800194"],"confidence":"High","gaps":["Specific Kv1.1-containing heteromer subtypes in carotid body not identified"]},{"year":2006,"claim":"Discovery that mTOR suppresses dendritic Kv1.1 translation introduced activity-dependent local synthesis as a mechanism for regulating dendritic excitability independently of axonal Kv1.1.","evidence":"Photoconvertible Kaede-Kv1.1 reporter for local synthesis; rapamycin treatment; surface biotinylation in hippocampal neurons","pmids":["17023663"],"confidence":"High","gaps":["Cis-regulatory elements in Kv1.1 mRNA mediating dendritic targeting not mapped"]},{"year":2008,"claim":"Demonstrating that Kvβ1 functions as an aldoketoreductase whose cofactor oxidation state controls Kv1.1 open-channel current linked cellular metabolic status to K⁺ channel conductance.","evidence":"In vitro enzymatic assay for Kvβ1; NADP⁺/H₂O₂ application during patch clamp; catalytic site mutagenesis","pmids":["18222921"],"confidence":"High","gaps":["Physiological substrates of Kvβ1 reductase in neurons not identified","In vivo metabolic conditions that trigger redox switching unclear"]},{"year":2009,"claim":"A KCNA1 N255D mutation causing autosomal dominant hypomagnesemia established a renal role for Kv1.1, showing it sets the membrane potential required for TRPM6-mediated Mg²⁺ reabsorption in the distal convoluted tubule.","evidence":"Positional cloning; immunolocalization in kidney; patch clamp showing dominant-negative loss of function","pmids":["19307729"],"confidence":"High","gaps":["Kv1.1 heteromer composition in DCT not determined","Mechanism by which membrane potential specifically couples to TRPM6 activity not fully resolved"]},{"year":2010,"claim":"Kcna1-null mice showed brain-driven cardiac arrhythmias reversed by atropine, identifying excessive parasympathetic outflow via Kv1.1-expressing vagus nerve juxtaparanodes as the mechanism linking Kv1.1 loss to cardiac dysfunction.","evidence":"Simultaneous video-EEG-ECG; selective autonomic blockade; vagus nerve immunohistochemistry","pmids":["20392939"],"confidence":"High","gaps":["Whether cardiac arrhythmias are purely ictal or also interictal not fully resolved","Role of respiratory dysfunction in SUDEP mechanism not dissected"]},{"year":2011,"claim":"RNA editing at I400V in the S6 segment was found to generate 4-AP-insensitive Kv1.1 channels, with editing upregulated in chronic epilepsy, suggesting an endogenous compensatory response to hyperexcitability.","evidence":"RNA editing quantification in kainic acid epilepsy model; electrophysiology of I400V channels in Xenopus oocytes","pmids":["21371023"],"confidence":"Medium","gaps":["ADAR enzyme responsible for I400V editing not identified","Functional impact of altered editing on seizure frequency not tested in vivo"]},{"year":2011,"claim":"V408A knock-in mice demonstrated that EA1 myokymia originates from spontaneous Ca²⁺ signals in motor nerve axons, independent of the neuromuscular junction, placing the pathogenic mechanism in the axon itself.","evidence":"In vivo nerve-muscle preparation; two-photon Ca²⁺ imaging; nerve axotomy experiments","pmids":["22609489"],"confidence":"High","gaps":["Molecular basis of aberrant Ca²⁺ entry in V408A axons not determined"]},{"year":2013,"claim":"Kv1.1 was identified as a mechanosensitive brake in C-fiber high-threshold mechanoreceptors: Kv1.1 in Kv1.1-Kv1.2 heteromers opposes slow MS cation currents to set mechanical firing threshold.","evidence":"Toxin profiling; transgenic mouse studies; DRG neuron patch clamp; behavioral mechanical allodynia assays","pmids":["23473320"],"confidence":"High","gaps":["Structural basis for mechanosensitivity of Kv1.1-containing heteromers unknown"]},{"year":2013,"claim":"Two competing translational regulators—miR-129 (repressor) and HuD (activator)—were shown to mediate mTOR-dependent control of dendritic Kv1.1 synthesis, refining the mechanism by which neuronal activity tunes local Kv1.1 levels.","evidence":"miRNA identification; HuD RNA-binding assays; polysome profiling; reporter assays in neurons","pmids":["23836929"],"confidence":"High","gaps":["Whether miR-129 and HuD binding sites overlap or are distinct on Kv1.1 3′-UTR not mapped"]},{"year":2013,"claim":"Loss of Kv1.1 in hippocampus increased presynaptic neurotransmitter release at mossy fiber and perforant path terminals, linking presynaptic Kv1.1 to circuit-level timing and pathological oscillations.","evidence":"Multielectrode array recordings in Kcna1-null hippocampal slices; DTX-κ pharmacology","pmids":["23466697"],"confidence":"High","gaps":["Whether increased release is purely due to spike broadening or also involves resting Ca²⁺ changes not resolved"]},{"year":2017,"claim":"Direct recording from small synaptic boutons showed that Kv1.1 controls basal presynaptic spike width, and that EA1 V408A heterozygosity abolishes analog modulation of spike width by somatic depolarization, revealing a novel disease mechanism.","evidence":"Scanning ion conductance microscopy of intact boutons; DTX-K; heterozygous V408A knock-in mice","pmids":["28193892"],"confidence":"High","gaps":["Subunit stoichiometry of native presynaptic Kv1 channels disrupted by V408A not directly measured"]},{"year":2018,"claim":"LGI1 autoantibodies were shown to reduce synaptic Kv1.1 levels before AMPA receptors, establishing Kv1.1 displacement from the LGI1-ADAM22/23 complex as an early driver of autoimmune neuronal hyperexcitability.","evidence":"Patient IgG cerebroventricular transfer in mice; confocal quantification; patch clamp and LTP recordings","pmids":["30346486"],"confidence":"High","gaps":["Mechanism of Kv1.1 removal from synaptic membrane (internalization vs. lateral diffusion) not determined"]},{"year":2020,"claim":"Neuron-specific conditional deletion proved that brain Kv1.1 loss—not cardiac-intrinsic deficiency—is sufficient for epilepsy and SUDEP-like cardiorespiratory failure, resolving the tissue origin of SUDEP risk.","evidence":"Floxed Kcna1 × Synapsin1-Cre conditional KO; EEG, ECG, plethysmography; survival analysis","pmids":["31978607"],"confidence":"High","gaps":["Specific brain circuits (brainstem vs. cortical) driving fatal cardiorespiratory collapse not dissected","Whether cerebellar Kv1.1 retention modulates SUDEP threshold confirmed only indirectly"]},{"year":null,"claim":"Key unresolved questions include: the high-resolution structural basis for EA1 mutation-specific gating defects, the identity and regulation of the palmitoyl acyltransferase(s) and ADAR(s) acting on Kv1.1, the precise subunit stoichiometry of native Kv1.1-containing heteromers at defined synapses, and the specific brainstem circuits through which Kv1.1 loss drives fatal cardiorespiratory arrest.","evidence":"","pmids":[],"confidence":"High","gaps":["No cryo-EM or X-ray structure of human Kv1.1 homomeric or heteromeric channel","Palmitoyl acyltransferase identity unknown","Circuit-level mechanism of SUDEP not resolved at cell-type specificity"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,3,5,8,13,14,17,25]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[29]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,17,19,24,31]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[22,31]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[14,18,20,26,27,30,37]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,5,8,24,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[19,28,34]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,5,10,24,39]}],"complexes":["Kv1.1-Kv1.2 heterotetramer","Kv1.1-Kv1.4 heterotetramer","Kv1.1/Kvβ1 complex"],"partners":["KCNA2","KCNA4","KCNAB1","KCNE4","LGI1","ADAM22","ADAM23","TRPM6"],"other_free_text":[]},"mechanistic_narrative":"KCNA1 encodes the voltage-gated potassium channel subunit Kv1.1, a delayed-rectifier that assembles into homo- and heterotetramers with other Shaker-family subunits (Kv1.2, Kv1.4) and accessory Kvβ subunits to dampen neuronal excitability, control action potential threshold and width, and ensure temporal precision of firing across sensory, motor, and autonomic circuits [PMID:8046438, PMID:12611922, PMID:14534254, PMID:28193892]. Channel gating is tuned by palmitoylation at C243 (modulating voltage sensing), sialic acid glycosylation, Kvβ1 aldoketoreductase-dependent cofactor oxidation, PKA-driven membrane translocation, and mTOR/miR-129-mediated translational control of dendritic Kv1.1 mRNA [PMID:15837928, PMID:8702582, PMID:18222921, PMID:12681381, PMID:23836929]. Loss-of-function mutations cause episodic ataxia type 1 with myokymia through dominant-negative or haploinsufficiency mechanisms, and certain mutations cause autosomal dominant hypomagnesemia by disrupting the membrane potential required for TRPM6-dependent Mg²⁺ reabsorption in the distal convoluted tubule [PMID:7842011, PMID:9526001, PMID:19307729]. Neuron-specific Kv1.1 deficiency is sufficient to produce seizures and sudden unexpected death in epilepsy (SUDEP) through brain-driven cardiorespiratory dysregulation involving excessive parasympathetic outflow via the vagus nerve [PMID:20392939, PMID:31978607]."},"prefetch_data":{"uniprot":{"accession":"Q09470","full_name":"Potassium voltage-gated channel subfamily A member 1","aliases":["Voltage-gated K(+) channel HuKI","Voltage-gated potassium channel HBK1","Voltage-gated potassium channel subunit Kv1.1"],"length_aa":495,"mass_kda":56.5,"function":"Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain and the central nervous system, but also in the kidney (PubMed:19903818, PubMed:8845167). Contributes to the regulation of the membrane potential and nerve signaling, and prevents neuronal hyperexcitability (PubMed:17156368). Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:19912772). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, KCNA6, KCNA7, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel (PubMed:12077175, PubMed:17156368). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation of delayed rectifier potassium channels (PubMed:12077175, PubMed:17156368). In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes, making it difficult to assign currents observed in intact tissues to any particular potassium channel family member. Homotetrameric KCNA1 forms a delayed-rectifier potassium channel that opens in response to membrane depolarization, followed by slow spontaneous channel closure (PubMed:19307729, PubMed:19903818, PubMed:19912772, PubMed:19968958). In contrast, a heterotetrameric channel formed by KCNA1 and KCNA4 shows rapid inactivation (PubMed:17156368). Regulates neuronal excitability in hippocampus, especially in mossy fibers and medial perforant path axons, preventing neuronal hyperexcitability. Response to toxins that are selective for KCNA1, respectively for KCNA2, suggests that heteromeric potassium channels composed of both KCNA1 and KCNA2 play a role in pacemaking and regulate the output of deep cerebellar nuclear neurons (By similarity). May function as down-stream effector for G protein-coupled receptors and inhibit GABAergic inputs to basolateral amygdala neurons (By similarity). May contribute to the regulation of neurotransmitter release, such as gamma-aminobutyric acid (GABA) release (By similarity). Plays a role in regulating the generation of action potentials and preventing hyperexcitability in myelinated axons of the vagus nerve, and thereby contributes to the regulation of heart contraction (By similarity). Required for normal neuromuscular responses (PubMed:11026449, PubMed:17136396). Regulates the frequency of neuronal action potential firing in response to mechanical stimuli, and plays a role in the perception of pain caused by mechanical stimuli, but does not play a role in the perception of pain due to heat stimuli (By similarity). Required for normal responses to auditory stimuli and precise location of sound sources, but not for sound perception (By similarity). The use of toxins that block specific channels suggest that it contributes to the regulation of the axonal release of the neurotransmitter dopamine (By similarity). Required for normal postnatal brain development and normal proliferation of neuronal precursor cells in the brain (By similarity). Plays a role in the reabsorption of Mg(2+) in the distal convoluted tubules in the kidney and in magnesium ion homeostasis, probably via its effect on the membrane potential (PubMed:19307729, PubMed:23903368)","subcellular_location":"Cell membrane; Membrane; Cell projection, axon; Cytoplasmic vesicle; Perikaryon; Endoplasmic reticulum; Cell projection, dendrite; Cell junction; Synapse; Presynaptic cell membrane; Presynapse","url":"https://www.uniprot.org/uniprotkb/Q09470/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KCNA1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KCNA1","total_profiled":1310},"omim":[{"mim_id":"619295","title":"ZDHHC PALMITOYLTRANSFERASE 14; ZDHHC14","url":"https://www.omim.org/entry/619295"},{"mim_id":"611725","title":"POTASSIUM CHANNEL TETRAMERIZATION DOMAIN-CONTAINING PROTEIN 7; KCTD7","url":"https://www.omim.org/entry/611725"},{"mim_id":"608302","title":"LEUCINE-RICH GENE, GLIOMA-INACTIVATED, 3; LGI3","url":"https://www.omim.org/entry/608302"},{"mim_id":"604619","title":"LEUCINE-RICH GENE, GLIOMA-INACTIVATED, 1; LGI1","url":"https://www.omim.org/entry/604619"},{"mim_id":"603788","title":"POTASSIUM CHANNEL, VOLTAGE-GATED, SUBFAMILY G, MEMBER 1; KCNG1","url":"https://www.omim.org/entry/603788"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":53.1}],"url":"https://www.proteinatlas.org/search/KCNA1"},"hgnc":{"alias_symbol":["Kv1.1","RBK1","HUK1","MBK1"],"prev_symbol":["AEMK"]},"alphafold":{"accession":"Q09470","domains":[{"cath_id":"3.30.710.10","chopping":"39-135","consensus_level":"high","plddt":95.1346,"start":39,"end":135},{"cath_id":"1.10.287.70","chopping":"314-424","consensus_level":"high","plddt":93.707,"start":314,"end":424},{"cath_id":"1.20.120","chopping":"149-309","consensus_level":"high","plddt":82.3611,"start":149,"end":309}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q09470","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q09470-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q09470-F1-predicted_aligned_error_v6.png","plddt_mean":78.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KCNA1","jax_strain_url":"https://www.jax.org/strain/search?query=KCNA1"},"sequence":{"accession":"Q09470","fasta_url":"https://rest.uniprot.org/uniprotkb/Q09470.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q09470/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q09470"}},"corpus_meta":[{"pmid":"7842011","id":"PMC_7842011","title":"Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1.","date":"1994","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7842011","citation_count":628,"is_preprint":false},{"pmid":"8046438","id":"PMC_8046438","title":"Localization of Kv1.1 and Kv1.2, two K channel proteins, to synaptic terminals, somata, and dendrites in the mouse brain.","date":"1994","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/8046438","citation_count":337,"is_preprint":false},{"pmid":"17023663","id":"PMC_17023663","title":"Activity- and mTOR-dependent suppression of Kv1.1 channel mRNA translation in dendrites.","date":"2006","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/17023663","citation_count":228,"is_preprint":false},{"pmid":"11026449","id":"PMC_11026449","title":"Clinical, genetic, and expression studies of mutations in the potassium channel gene KCNA1 reveal new phenotypic variability.","date":"2000","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/11026449","citation_count":191,"is_preprint":false},{"pmid":"20392939","id":"PMC_20392939","title":"Kv1.1 potassium channel deficiency reveals brain-driven cardiac dysfunction as a candidate mechanism for sudden unexplained death in epilepsy.","date":"2010","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20392939","citation_count":184,"is_preprint":false},{"pmid":"30346486","id":"PMC_30346486","title":"LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory.","date":"2018","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/30346486","citation_count":182,"is_preprint":false},{"pmid":"19706400","id":"PMC_19706400","title":"Reduction of seizures by transplantation of cortical GABAergic interneuron precursors into Kv1.1 mutant mice.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19706400","citation_count":177,"is_preprint":false},{"pmid":"22158511","id":"PMC_22158511","title":"Neuregulin 1 regulates excitability of fast-spiking neurons through Kv1.1 and acts in epilepsy.","date":"2011","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/22158511","citation_count":152,"is_preprint":false},{"pmid":"12611922","id":"PMC_12611922","title":"Hyperexcitability and reduced low threshold potassium currents in auditory neurons of mice lacking the channel subunit Kv1.1.","date":"2003","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12611922","citation_count":119,"is_preprint":false},{"pmid":"23473320","id":"PMC_23473320","title":"Kv1.1 channels act as mechanical brake in the senses of touch and pain.","date":"2013","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/23473320","citation_count":110,"is_preprint":false},{"pmid":"19307729","id":"PMC_19307729","title":"A missense mutation in the Kv1.1 voltage-gated potassium channel-encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia.","date":"2009","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/19307729","citation_count":110,"is_preprint":false},{"pmid":"8126562","id":"PMC_8126562","title":"The brain Kv1.1 potassium channel: in vitro and in vivo studies on subunit assembly and posttranslational processing.","date":"1994","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/8126562","citation_count":108,"is_preprint":false},{"pmid":"23836929","id":"PMC_23836929","title":"Degradation of high affinity HuD targets releases Kv1.1 mRNA from miR-129 repression by mTORC1.","date":"2013","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23836929","citation_count":98,"is_preprint":false},{"pmid":"12042352","id":"PMC_12042352","title":"Potassium channels Kv1.1, Kv1.2 and Kv1.6 influence excitability of rat visceral sensory neurons.","date":"2002","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12042352","citation_count":98,"is_preprint":false},{"pmid":"14688283","id":"PMC_14688283","title":"Glycosylation affects the protein stability and cell surface expression of Kv1.4 but Not Kv1.1 potassium channels. A pore region determinant dictates the effect of glycosylation on trafficking.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14688283","citation_count":94,"is_preprint":false},{"pmid":"14534254","id":"PMC_14534254","title":"Decreased temporal precision of auditory signaling in Kcna1-null mice: an electrophysiological study in vivo.","date":"2003","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/14534254","citation_count":93,"is_preprint":false},{"pmid":"22612818","id":"PMC_22612818","title":"Kv1.1 and Kv1.2: similar channels, different seizure models.","date":"2012","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/22612818","citation_count":92,"is_preprint":false},{"pmid":"11097830","id":"PMC_11097830","title":"KV1.1 K(+) channels identification in human breast carcinoma cells: involvement in cell proliferation.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11097830","citation_count":79,"is_preprint":false},{"pmid":"9526001","id":"PMC_9526001","title":"Episodic ataxia mutations in Kv1.1 alter potassium channel function by dominant negative effects or haploinsufficiency.","date":"1998","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/9526001","citation_count":79,"is_preprint":false},{"pmid":"21106501","id":"PMC_21106501","title":"Nerve excitability studies characterize Kv1.1 fast potassium channel dysfunction in patients with episodic ataxia type 1.","date":"2010","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/21106501","citation_count":79,"is_preprint":false},{"pmid":"10575255","id":"PMC_10575255","title":"Developmental seizure susceptibility of kv1.1 potassium channel knockout mice.","date":"1999","source":"Developmental neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/10575255","citation_count":78,"is_preprint":false},{"pmid":"26446112","id":"PMC_26446112","title":"Orexin Receptor Antagonism Improves Sleep and Reduces Seizures in Kcna1-null Mice.","date":"2016","source":"Sleep","url":"https://pubmed.ncbi.nlm.nih.gov/26446112","citation_count":74,"is_preprint":false},{"pmid":"14755528","id":"PMC_14755528","title":"Activity-dependent regulation of the potassium channel subunits Kv1.1 and Kv3.1.","date":"2004","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/14755528","citation_count":74,"is_preprint":false},{"pmid":"32331416","id":"PMC_32331416","title":"Kv1.1 Channelopathies: Pathophysiological Mechanisms and Therapeutic Approaches.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32331416","citation_count":73,"is_preprint":false},{"pmid":"8702582","id":"PMC_8702582","title":"Expression of Kv1.1 delayed rectifier potassium channels in Lec mutant Chinese hamster ovary cell lines reveals a role for sialidation in channel function.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8702582","citation_count":73,"is_preprint":false},{"pmid":"32316562","id":"PMC_32316562","title":"Clinical Spectrum of KCNA1 Mutations: New Insights into Episodic Ataxia and Epilepsy Comorbidity.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32316562","citation_count":68,"is_preprint":false},{"pmid":"16672305","id":"PMC_16672305","title":"Kv1.1-containing channels are critical for temporal precision during spike initiation.","date":"2006","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/16672305","citation_count":67,"is_preprint":false},{"pmid":"10428758","id":"PMC_10428758","title":"Mutations in the KCNA1 gene associated with episodic ataxia type-1 syndrome impair heteromeric voltage-gated K(+) channel function.","date":"1999","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/10428758","citation_count":65,"is_preprint":false},{"pmid":"12944270","id":"PMC_12944270","title":"KCNE4 is an inhibitory subunit to Kv1.1 and Kv1.3 potassium channels.","date":"2003","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/12944270","citation_count":64,"is_preprint":false},{"pmid":"23466697","id":"PMC_23466697","title":"Loss of the Kv1.1 potassium channel promotes pathologic sharp waves and high frequency oscillations in in vitro hippocampal slices.","date":"2013","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/23466697","citation_count":61,"is_preprint":false},{"pmid":"17855588","id":"PMC_17855588","title":"Manipulation of the potassium channel Kv1.1 and its effect on neuronal excitability in rat sensory neurons.","date":"2007","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/17855588","citation_count":58,"is_preprint":false},{"pmid":"15837928","id":"PMC_15837928","title":"The human Kv1.1 channel is palmitoylated, modulating voltage sensing: Identification of a palmitoylation consensus sequence.","date":"2005","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15837928","citation_count":58,"is_preprint":false},{"pmid":"17651419","id":"PMC_17651419","title":"Structural consequences of Kcna1 gene deletion and transfer in the mouse hippocampus.","date":"2007","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/17651419","citation_count":57,"is_preprint":false},{"pmid":"11389194","id":"PMC_11389194","title":"Functional and molecular expression of a voltage-dependent K(+) channel (Kv1.1) in interstitial cells of Cajal.","date":"2001","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/11389194","citation_count":55,"is_preprint":false},{"pmid":"11679591","id":"PMC_11679591","title":"Episodic ataxia type-1 mutations in the Kv1.1 potassium channel display distinct folding and intracellular trafficking properties.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11679591","citation_count":54,"is_preprint":false},{"pmid":"18222921","id":"PMC_18222921","title":"Functional coupling between the Kv1.1 channel and aldoketoreductase Kvbeta1.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18222921","citation_count":52,"is_preprint":false},{"pmid":"19696788","id":"PMC_19696788","title":"Kv1.1 and Kv1.3 channels contribute to the degeneration of retinal ganglion cells after optic nerve transection in vivo.","date":"2010","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/19696788","citation_count":52,"is_preprint":false},{"pmid":"11773313","id":"PMC_11773313","title":"Variable K(+) channel subunit dysfunction in inherited mutations of KCNA1.","date":"2002","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/11773313","citation_count":51,"is_preprint":false},{"pmid":"9600245","id":"PMC_9600245","title":"Three novel KCNA1 mutations in episodic ataxia type I families.","date":"1998","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9600245","citation_count":50,"is_preprint":false},{"pmid":"17156368","id":"PMC_17156368","title":"Episodic ataxia type 1 mutations in the KCNA1 gene impair the fast inactivation properties of the human potassium channels Kv1.4-1.1/Kvbeta1.1 and Kv1.4-1.1/Kvbeta1.2.","date":"2006","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/17156368","citation_count":50,"is_preprint":false},{"pmid":"18937510","id":"PMC_18937510","title":"Different residues in channel turret determining the selectivity of ADWX-1 inhibitor peptide between Kv1.1 and Kv1.3 channels.","date":"2008","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/18937510","citation_count":50,"is_preprint":false},{"pmid":"26825872","id":"PMC_26825872","title":"Distinctive role of KV1.1 subunit in the biology and functions of low threshold K(+) channels with implications for neurological disease.","date":"2016","source":"Pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/26825872","citation_count":49,"is_preprint":false},{"pmid":"9718989","id":"PMC_9718989","title":"Hyperalgesia in mice lacking the Kv1.1 potassium channel gene.","date":"1998","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/9718989","citation_count":49,"is_preprint":false},{"pmid":"7852365","id":"PMC_7852365","title":"Concomitant acceleration of the activation and inactivation kinetics of the human delayed rectifier K+ channel (Kv1.1) by Ca(2+)-independent phospholipase A2.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7852365","citation_count":49,"is_preprint":false},{"pmid":"16306173","id":"PMC_16306173","title":"Mu opioid receptor activation inhibits GABAergic inputs to basolateral amygdala neurons through Kv1.1/1.2 channels.","date":"2005","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/16306173","citation_count":49,"is_preprint":false},{"pmid":"29327348","id":"PMC_29327348","title":"Respiratory dysfunction progresses with age in Kcna1-null mice, a model of sudden unexpected death in epilepsy.","date":"2018","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/29327348","citation_count":48,"is_preprint":false},{"pmid":"14686897","id":"PMC_14686897","title":"Truncation of the Shaker-like voltage-gated potassium channel, Kv1.1, causes megencephaly.","date":"2003","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/14686897","citation_count":48,"is_preprint":false},{"pmid":"10409113","id":"PMC_10409113","title":"Protein kinase C inhibits Kv1.1 potassium channel function.","date":"1999","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10409113","citation_count":48,"is_preprint":false},{"pmid":"18088316","id":"PMC_18088316","title":"A cysteine-rich receptor-like kinase NCRK and a pathogen-induced protein kinase RBK1 are Rop GTPase interactors.","date":"2007","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18088316","citation_count":47,"is_preprint":false},{"pmid":"9671659","id":"PMC_9671659","title":"Expression of Kv1.1, a Shaker-like potassium channel, is temporally regulated in embryonic neurons and glia.","date":"1998","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/9671659","citation_count":47,"is_preprint":false},{"pmid":"18424000","id":"PMC_18424000","title":"In the ventral cochlear nucleus Kv1.1 and subunits of HCN1 are colocalized at surfaces of neurons that have low-voltage-activated and hyperpolarization-activated conductances.","date":"2008","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/18424000","citation_count":47,"is_preprint":false},{"pmid":"9714564","id":"PMC_9714564","title":"Characterization of three episodic ataxia mutations in the human Kv1.1 potassium channel.","date":"1998","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/9714564","citation_count":45,"is_preprint":false},{"pmid":"29415410","id":"PMC_29415410","title":"Functional role of Kv1.1 and Kv1.3 channels in the neoplastic progression steps of three cancer cell lines, elucidated by scorpion peptides.","date":"2018","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/29415410","citation_count":45,"is_preprint":false},{"pmid":"31978607","id":"PMC_31978607","title":"Neuron-specific Kv1.1 deficiency is sufficient to cause epilepsy, premature death, and cardiorespiratory dysregulation.","date":"2020","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/31978607","citation_count":44,"is_preprint":false},{"pmid":"23774215","id":"PMC_23774215","title":"Potassium channel KCNA1 modulates oncogene-induced senescence and transformation.","date":"2013","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/23774215","citation_count":43,"is_preprint":false},{"pmid":"28334922","id":"PMC_28334922","title":"Scn2a deletion improves survival and brain-heart dynamics in the Kcna1-null mouse model of sudden unexpected death in epilepsy (SUDEP).","date":"2017","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28334922","citation_count":43,"is_preprint":false},{"pmid":"19205071","id":"PMC_19205071","title":"A novel KCNA1 mutation associated with global delay and persistent cerebellar dysfunction.","date":"2009","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/19205071","citation_count":41,"is_preprint":false},{"pmid":"25792741","id":"PMC_25792741","title":"Variability of Potassium Channel Blockers in Mesobuthus eupeus Scorpion Venom with Focus on Kv1.1: AN INTEGRATED TRANSCRIPTOMIC AND PROTEOMIC STUDY.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25792741","citation_count":41,"is_preprint":false},{"pmid":"25270294","id":"PMC_25270294","title":"Rapamycin reveals an mTOR-independent repression of Kv1.1 expression during epileptogenesis.","date":"2014","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/25270294","citation_count":39,"is_preprint":false},{"pmid":"29294000","id":"PMC_29294000","title":"Familial paroxysmal kinesigenic dyskinesia is associated with mutations in the KCNA1 gene.","date":"2018","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29294000","citation_count":39,"is_preprint":false},{"pmid":"25642194","id":"PMC_25642194","title":"Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene.","date":"2015","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25642194","citation_count":39,"is_preprint":false},{"pmid":"24367293","id":"PMC_24367293","title":"Regulation of action potential delays via voltage-gated potassium Kv1.1 channels in dentate granule cells during hippocampal epilepsy.","date":"2013","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24367293","citation_count":38,"is_preprint":false},{"pmid":"14602579","id":"PMC_14602579","title":"Kv1.1 and Kv1.3 channels contribute to the delayed-rectifying K+ conductance in rat choroid plexus epithelial cells.","date":"2003","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/14602579","citation_count":38,"is_preprint":false},{"pmid":"7673227","id":"PMC_7673227","title":"Identification of Kv1.1 expression by murine CD4-CD8- thymocytes. A role for voltage-dependent K+ channels in murine thymocyte development.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7673227","citation_count":37,"is_preprint":false},{"pmid":"18926884","id":"PMC_18926884","title":"A novel KCNA1 mutation identified in an Italian family affected by episodic ataxia type 1.","date":"2008","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/18926884","citation_count":36,"is_preprint":false},{"pmid":"21371023","id":"PMC_21371023","title":"RNA editing of Kv1.1 channels may account for reduced ictogenic potential of 4-aminopyridine in chronic epileptic rats.","date":"2011","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/21371023","citation_count":36,"is_preprint":false},{"pmid":"15800194","id":"PMC_15800194","title":"Kv1.1 deletion augments the afferent hypoxic chemosensory pathway and respiration.","date":"2005","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/15800194","citation_count":36,"is_preprint":false},{"pmid":"8020965","id":"PMC_8020965","title":"Genomic organization, nucleotide sequence, biophysical properties, and localization of the voltage-gated K+ channel gene KCNA4/Kv1.4 to mouse chromosome 2/human 11p14 and mapping of KCNC1/Kv3.1 to mouse 7/human 11p14.3-p15.2 and KCNA1/Kv1.1 to human 12p13.","date":"1994","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8020965","citation_count":36,"is_preprint":false},{"pmid":"31586945","id":"PMC_31586945","title":"Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia.","date":"2019","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31586945","citation_count":35,"is_preprint":false},{"pmid":"14636320","id":"PMC_14636320","title":"Hyperexcitability of CA3 pyramidal cells in mice lacking the potassium channel subunit Kv1.1.","date":"2003","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/14636320","citation_count":34,"is_preprint":false},{"pmid":"26162324","id":"PMC_26162324","title":"Expression and function of Kv1.1 potassium channels in human atria from patients with atrial fibrillation.","date":"2015","source":"Basic research in cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/26162324","citation_count":34,"is_preprint":false},{"pmid":"17869444","id":"PMC_17869444","title":"Kv1.1/1.2 channels are downstream effectors of nitric oxide on synaptic GABA release to preautonomic neurons in the paraventricular nucleus.","date":"2007","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/17869444","citation_count":34,"is_preprint":false},{"pmid":"19903818","id":"PMC_19903818","title":"Functional analysis of the Kv1.1 N255D mutation associated with autosomal dominant hypomagnesemia.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19903818","citation_count":32,"is_preprint":false},{"pmid":"29476105","id":"PMC_29476105","title":"mTOR-dependent alterations of Kv1.1 subunit expression in the neuronal subset-specific Pten knockout mouse model of cortical dysplasia with epilepsy.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29476105","citation_count":32,"is_preprint":false},{"pmid":"15532032","id":"PMC_15532032","title":"A novel mutation in KCNA1 causes episodic ataxia without myokymia.","date":"2004","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/15532032","citation_count":32,"is_preprint":false},{"pmid":"9636212","id":"PMC_9636212","title":"Cyclic AMP regulates potassium channel expression in C6 glioma by destabilizing Kv1.1 mRNA.","date":"1998","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9636212","citation_count":30,"is_preprint":false},{"pmid":"30055040","id":"PMC_30055040","title":"De novo KCNA1 variants in the PVP motif cause infantile epileptic encephalopathy and cognitive impairment similar to recurrent KCNA2 variants.","date":"2018","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/30055040","citation_count":30,"is_preprint":false},{"pmid":"17136396","id":"PMC_17136396","title":"Functional analysis of a novel potassium channel (KCNA1) mutation in hereditary myokymia.","date":"2006","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/17136396","citation_count":30,"is_preprint":false},{"pmid":"32030748","id":"PMC_32030748","title":"Progressive cardiorespiratory dysfunction in Kv1.1 knockout mice may provide temporal biomarkers of pending sudden unexpected death in epilepsy (SUDEP): The contribution of orexin.","date":"2020","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/32030748","citation_count":30,"is_preprint":false},{"pmid":"1533613","id":"PMC_1533613","title":"Identification of RBK1 potassium channels in C6 astrocytoma cells.","date":"1992","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/1533613","citation_count":29,"is_preprint":false},{"pmid":"22609489","id":"PMC_22609489","title":"Kv1.1 knock-in ataxic mice exhibit spontaneous myokymic activity exacerbated by fatigue, ischemia and low temperature.","date":"2012","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/22609489","citation_count":29,"is_preprint":false},{"pmid":"18226531","id":"PMC_18226531","title":"Disruption of Kv1.1 N-type inactivation by novel small molecule inhibitors (disinactivators).","date":"2007","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18226531","citation_count":29,"is_preprint":false},{"pmid":"22206926","id":"PMC_22206926","title":"Kcna1-mutant rats dominantly display myokymia, neuromyotonia and spontaneous epileptic seizures.","date":"2011","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/22206926","citation_count":28,"is_preprint":false},{"pmid":"17912752","id":"PMC_17912752","title":"Novel mutation in KCNA1 causes episodic ataxia with paroxysmal dyspnea.","date":"2008","source":"Muscle & nerve","url":"https://pubmed.ncbi.nlm.nih.gov/17912752","citation_count":28,"is_preprint":false},{"pmid":"21224222","id":"PMC_21224222","title":"Low-voltage activated Kv1.1 subunits are crucial for the processing of sound source location in the lateral superior olive in mice.","date":"2011","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21224222","citation_count":28,"is_preprint":false},{"pmid":"12077175","id":"PMC_12077175","title":"Episodic ataxia type 1 mutations in the human Kv1.1 potassium channel alter hKvbeta 1-induced N-type inactivation.","date":"2002","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/12077175","citation_count":28,"is_preprint":false},{"pmid":"26395884","id":"PMC_26395884","title":"Clinical heterogeneity associated with KCNA1 mutations include cataplexy and nonataxic presentations.","date":"2015","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/26395884","citation_count":26,"is_preprint":false},{"pmid":"12681381","id":"PMC_12681381","title":"Analysis of phosphorylation-dependent modulation of Kv1.1 potassium channels.","date":"2003","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/12681381","citation_count":26,"is_preprint":false},{"pmid":"17044011","id":"PMC_17044011","title":"Block of neural Kv1.1 potassium channels for neuroinflammatory disease therapy.","date":"2006","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/17044011","citation_count":26,"is_preprint":false},{"pmid":"7602512","id":"PMC_7602512","title":"Inactivation of the cloned potassium channel mouse Kv1.1 by the human Kv3.4 'ball' peptide and its chemical modification.","date":"1995","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/7602512","citation_count":26,"is_preprint":false},{"pmid":"31354026","id":"PMC_31354026","title":"Silencing of KCNA1 suppresses the cervical cancer development via mitochondria damage.","date":"2019","source":"Channels (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/31354026","citation_count":25,"is_preprint":false},{"pmid":"16331678","id":"PMC_16331678","title":"Involvement of Kv1.1 and Nav1.5 in proliferation of gastric epithelial cells.","date":"2006","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16331678","citation_count":25,"is_preprint":false},{"pmid":"12761827","id":"PMC_12761827","title":"Expression of the Kv1.1 ion channel subunit in the auditory brainstem of the big brown bat, Eptesicus fuscus.","date":"2003","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/12761827","citation_count":25,"is_preprint":false},{"pmid":"19118603","id":"PMC_19118603","title":"Kv1.1 expression in microglia regulates production and release of proinflammatory cytokines, endothelins and nitric oxide.","date":"2008","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/19118603","citation_count":25,"is_preprint":false},{"pmid":"16956965","id":"PMC_16956965","title":"Episodic ataxia type 1 mutation F184C alters Zn2+-induced modulation of the human K+ channel Kv1.4-Kv1.1/Kvbeta1.1.","date":"2006","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16956965","citation_count":25,"is_preprint":false},{"pmid":"22396426","id":"PMC_22396426","title":"Kcna1 gene deletion lowers the behavioral sensitivity of mice to small changes in sound location and increases asynchronous brainstem auditory evoked potentials but does not affect hearing thresholds.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/22396426","citation_count":24,"is_preprint":false},{"pmid":"27271339","id":"PMC_27271339","title":"A novel KCNA1 mutation in a family with episodic ataxia and malignant hyperthermia.","date":"2016","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/27271339","citation_count":23,"is_preprint":false},{"pmid":"18365869","id":"PMC_18365869","title":"KCNA1 and TRPC6 ion channels and NHE1 exchanger operate the biological outcome of HGF/scatter factor in renal tubular cells.","date":"2007","source":"Growth factors (Chur, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/18365869","citation_count":23,"is_preprint":false},{"pmid":"28666963","id":"PMC_28666963","title":"A novel KCNA1 mutation in a patient with paroxysmal ataxia, myokymia, painful contractures and metabolic dysfunctions.","date":"2017","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/28666963","citation_count":23,"is_preprint":false},{"pmid":"28193892","id":"PMC_28193892","title":"Kv1.1 channelopathy abolishes presynaptic spike width modulation by subthreshold somatic depolarization.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28193892","citation_count":23,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51948,"output_tokens":9849,"usd":0.151789},"stage2":{"model":"claude-opus-4-6","input_tokens":13834,"output_tokens":5210,"usd":0.29913},"total_usd":0.450919,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"KCNA1 (Kv1.1) missense point mutations in heterozygous state cause episodic ataxia/myokymia syndrome, establishing KCNA1 as the disease gene for EA1\",\n      \"method\": \"Mutation analysis of KCNA1 coding region in EA1 families; heterologous expression\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — foundational genetic + functional study, replicated across multiple families and labs\",\n      \"pmids\": [\"7842011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Kv1.1 protein localizes to synaptic terminals, juxta-paranodal regions of myelinated axons, unmyelinated axons, cell somata, and proximal dendrites in mouse brain\",\n      \"method\": \"Immunocytochemistry/immunohistochemistry with isoform-specific antisera in mouse brain\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with isoform-specific antibodies, highly cited foundational study\",\n      \"pmids\": [\"8046438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Kv1.1 assembles cotranslationally with other Shaker-like subunits (e.g., Kv1.4) but not with non-Shaker subunits (Kv2.1); N207 glycosylation occurs but is not required for assembly, transport, or function; channel appears as 57–59 kDa doublet reflecting posttranslational processing\",\n      \"method\": \"Co-immunoprecipitation from in vitro translations and transfected cells; pulse-chase metabolic labeling; site-directed mutagenesis of glycosylation site; electrophysiology\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with co-IP and mutagenesis in a single rigorous study\",\n      \"pmids\": [\"8126562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Ca2+-independent phospholipase A2 modulates Kv1.1 channel kinetics through release of arachidonic acid, which accelerates both activation and induces inactivation of Kv1.1 currents\",\n      \"method\": \"Intracellular administration of PLA2 and exogenous arachidonic acid in Sf9 cells expressing Kv1.1; whole-cell patch clamp; mechanism-based PLA2 inhibitor controls\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with enzymatic and chemical controls, multiple orthogonal approaches\",\n      \"pmids\": [\"7852365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Sialic acid addition to Kv1.1 modulates voltage dependence of activation by influencing the local electric field at the voltage sensor; sialidase treatment or elevated Ca2+ shifts activation to more positive voltages, mimicking effects seen in glycosylation-deficient cell lines\",\n      \"method\": \"Expression in Lec mutant CHO cells deficient in glycosylation; sialidase treatment; whole-cell patch clamp\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution in glycosylation mutant lines with pharmacological validation\",\n      \"pmids\": [\"8702582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"EA1 mutations in Kv1.1 impair channel function by two distinct mechanisms: dominant negative effects (most mutations form heteromeric channels with intermediate properties) or haploinsufficiency (R239S and F249I yield minimal protein and current)\",\n      \"method\": \"Heterologous expression in Xenopus oocytes; TEA-tagging to distinguish subunit contributions; Western blot for protein levels\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis with pharmacological subunit discrimination and protein quantification\",\n      \"pmids\": [\"9526001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Kv1.1 knockout mice exhibit hyperalgesia (reduced nociceptive thresholds in paw flick, hot plate, and formalin assays) and blunted morphine antinociception, establishing Kv1.1 as a regulator of nociceptive and antinociceptive signaling\",\n      \"method\": \"Behavioral pain assays in Kcna1-null mice (-/-) versus heterozygous (+/-) and wild-type (+/+) littermates\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined behavioral phenotype across multiple pain assays\",\n      \"pmids\": [\"9718989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Kv1.1 mRNA is destabilized by cAMP elevation in C6 glioma cells, reducing Kv1.1 protein and outward K+ current, and thereby depolarizing resting membrane potential\",\n      \"method\": \"cAMP elevation by pharmacological agents; Northern blot for RNA decay; Western blot; whole-cell patch clamp; dendrotoxin-I pharmacology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods in single lab, functional consequence demonstrated\",\n      \"pmids\": [\"9636212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"EA1 mutations V408A and E325D in Kv1.1 co-assemble with Kv1.2 to form heteromeric channels with altered kinetics of activation, deactivation, C-type inactivation, and voltage dependence; V408A reduces mean single-channel open duration ~3-fold\",\n      \"method\": \"Tandemly linked subunits expressed in Xenopus oocytes; single-channel and macroscopic patch clamp analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — tandem-linked subunit constructs with single-channel analysis providing mechanistic detail\",\n      \"pmids\": [\"10428758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Protein kinase C activation inhibits Kv1.1 current by a mechanism requiring a C3 exoenzyme substrate (Rho GTPase pathway) but does not alter channel gating kinetics or promote channel internalization; inhibition is not via direct phosphorylation of Kv1.1\",\n      \"method\": \"PMA application in Xenopus oocytes; PKC inhibitors; site-directed mutagenesis of PKC sites; Western blot; botulinum toxin C3 injection\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis plus pharmacological dissection in single lab\",\n      \"pmids\": [\"10409113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Four EA1 KCNA1 mutations impair delayed-rectifier K+ currents by different mechanisms: some alter gating properties, others cause truncation with dominant negative effects; phenotypic variability correlates with degree and nature of channel dysfunction\",\n      \"method\": \"Heterologous expression in Xenopus oocytes; electrophysiology; confocal microscopy of GFP-tagged subunits\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple mutations characterized with electrophysiology and imaging\",\n      \"pmids\": [\"11026449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"EA1 missense mutations generate Kv1.1 subunits with normal folding and trafficking, whereas the nonsense truncation mutation causes intracellular aggregation and detergent insolubility that can be transferred to co-assembled Kv1 α- and Kvβ-subunits\",\n      \"method\": \"Immunocytochemistry; detergent solubility assays; co-assembly studies in heterologous cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods in single lab demonstrating distinct trafficking phenotypes\",\n      \"pmids\": [\"11679591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"EA1 mutation R417stop (C-terminal truncation) impairs both tetramerization of Kv1.1 with wild-type subunits and membrane targeting of heterotetramers, while typical EA1 mutations (e.g., V404I, P244H) affect only channel kinetics without disrupting assembly or trafficking\",\n      \"method\": \"Co-expression in Xenopus oocytes; pharmacological discrimination of subunit contribution; confocal imaging of GFP-tagged subunits\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple complementary approaches with pharmacological subunit tagging and imaging\",\n      \"pmids\": [\"11773313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"EA1 mutations E325D and V408A destabilize the open state of Kv1.1, increasing deactivation rates ~10-fold, and alter Kvβ1-induced N-type inactivation: inactivation onset is ~2-fold slower and recovery is ~10-fold faster than wild-type\",\n      \"method\": \"Heterologous expression with Kvβ1 in Xenopus oocytes; macroscopic and gating current recording; comparison of homomeric and heteromeric channels\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — rigorous electrophysiological characterization with systematic stoichiometry controls\",\n      \"pmids\": [\"12077175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Kv1.1 subunits contribute approximately half the low-threshold IKL current in auditory MNTB neurons; absence of Kv1.1 (Kcna1-null) reduces IKL amplitude by ~50% and doubles neuronal excitability (more APs, halved threshold current); residual IKL is DTX-sensitive, suggesting Kv1.2/Kv1.6 compensation\",\n      \"method\": \"Whole-cell patch clamp in brainstem slices from Kcna1-null and wild-type mice; DTX pharmacology\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with quantitative electrophysiology and pharmacological dissection\",\n      \"pmids\": [\"12611922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Glycosylation at the S1-S2 linker affects Kv1.1 gating function but, unlike Kv1.4, does not influence protein stability or cell-surface expression; a pore-region determinant dictates differential glycosylation effects on trafficking between Kv1.1 and Kv1.4\",\n      \"method\": \"N-glycosylation mutants; cell-surface biotinylation; immunocytochemistry; electrophysiology in transfected cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — chimeric channel strategy with mutagenesis identifies pore-region determinant\",\n      \"pmids\": [\"14688283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"KCNA1 11-bp deletion (mceph mouse) produces a truncated Kv1.1 that retains only N-terminal assembly domains, sequesters Kv1.2 and Kv1.3 subunits, reduces their protein levels in hippocampus, and causes seizures and megalencephaly\",\n      \"method\": \"Positional cloning; immunoblot for Kv1.2 and Kv1.3; immunohistochemistry; EEG\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic model with protein biochemistry demonstrating dominant-negative sequestration\",\n      \"pmids\": [\"14686897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human Kv1.1 is palmitoylated at C243 in the S2-S3 cytosolic linker; preventing palmitoylation at C243 causes a 20-mV leftward shift in the current-voltage relationship, indicating palmitoylation modulates voltage sensing\",\n      \"method\": \"[3H]palmitate radiolabeling; chemical stability studies; site-directed mutagenesis; whole-cell patch clamp in Sf9 cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with radiolabeling, mutagenesis, and functional electrophysiology\",\n      \"pmids\": [\"15837928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Absence of Kv1.1 in Kcna1-null mice reduces temporal precision of auditory signaling: increased first-spike latency jitter in VCN bushy cells, calyceal terminals, and MNTB neurons in vivo, and reduced ability to follow high-frequency amplitude-modulated stimulation\",\n      \"method\": \"In vivo single-unit recordings from VCN and MNTB neurons in Kcna1-null vs. wild-type mice\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with in vivo electrophysiology across multiple auditory stations\",\n      \"pmids\": [\"14534254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"mTOR activity suppresses Kv1.1 mRNA translation in dendrites; inhibition of mTOR (rapamycin) or NMDA receptors increases dendritic Kv1.1 protein and surface expression without altering axonal expression; endogenous Kv1.1 mRNA is present in dendrites\",\n      \"method\": \"Live imaging of Kaede-Kv1.1 reporter for local synthesis; rapamycin treatment; surface biotinylation; immunostaining in hippocampal neurons\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — photoconvertible reporter for local synthesis plus pharmacological dissection, multiple orthogonal methods\",\n      \"pmids\": [\"17023663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Kv1.1-containing channels (identified by DTX-K) underlie IKL in MNTB neurons and are critical for temporal precision of action potential initiation; pharmacological or genetic reduction of Kv1.1 increases AP latency jitter, particularly during rapid stimulation (100-500 Hz)\",\n      \"method\": \"Pharmacology with DTX-K at selective concentrations; whole-cell patch clamp in Kcna1-/- mouse brain slices; comparison of genetic and pharmacological IKL reduction\",\n      \"journal\": \"Journal of neurophysiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — parallel pharmacological and genetic approaches yield concordant results\",\n      \"pmids\": [\"16672305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"EA1 mutations E325D, V404I, V408A, and I177N alter N-type inactivation and repriming properties of heteromeric Kv1.4-Kv1.1/Kvβ1.1 and Kv1.4-Kv1.1/Kvβ1.2 channels, decreasing inactivation rate and accelerating recovery from inactivation\",\n      \"method\": \"Tandemly linked subunits in Xenopus oocytes; two-electrode voltage clamp\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — tandem-linked constructs isolating subunit contributions with systematic mutation analysis\",\n      \"pmids\": [\"17156368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PKA activation phosphorylates intracellular Kv1.1 protein and promotes its rapid translocation to the plasma membrane, increasing current amplitude and altering voltage dependence of activation; PKC activation does not directly phosphorylate Kv1.1 but induces Kv1.1 protein synthesis\",\n      \"method\": \"Patch clamp in stably transfected HEK293 cells; PKA/PKC activators; phosphorylation assays\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods in single lab demonstrating PKA-dependent translocation and functional change\",\n      \"pmids\": [\"12681381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Kvβ1 is a functional aldoketoreductase; oxidation of Kvβ1-bound NADPH cofactor (enzymatically or by H2O2/NADP+) induces a large increase in Kv1.1 open-channel current; the rate of cofactor oxidation is regulated by membrane potential (~2-fold faster at 0 mV vs. -100 mV), linking metabolic state to channel function\",\n      \"method\": \"In vitro aldoketoreductase assay for Kvβ1; electrophysiology with NADP+/H2O2 application; site-directed mutagenesis of catalytic site; whole-cell patch clamp\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — enzymatic reconstitution combined with electrophysiology and mutagenesis\",\n      \"pmids\": [\"18222921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A KCNA1 N255D mutation causes autosomal dominant hypomagnesemia; Kv1.1 is expressed in the distal convoluted tubule where it colocalizes with TRPM6 at the luminal membrane, and N255D produces a non-functional channel with dominant negative effect on wild-type Kv1.1, disrupting the membrane potential needed for TRPM6-mediated Mg2+ reabsorption\",\n      \"method\": \"Positional cloning; immunolocalization in kidney; patch clamp in human kidney cell line; overexpression studies\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — positional cloning plus patch clamp and colocalization providing pathway mechanism\",\n      \"pmids\": [\"19307729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Asparagine at position 255 in the S3 transmembrane segment of Kv1.1 is essential for normal voltage dependence and gating kinetics; charged or bulky substitutions (N255D, N255E, N255Q) abolish ion conduction while other substitutions shift activation to more negative potentials and alter kinetics\",\n      \"method\": \"Systematic mutagenesis at N255; cell surface biotinylation; whole-cell patch clamp in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis with electrophysiology characterizing structure-function at a specific residue\",\n      \"pmids\": [\"19903818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Kv1.1 deficiency (Kcna1-null) causes brain-driven cardiac dysfunction including AV conduction blocks, bradycardia, and premature ventricular contractions; these arise from excessive parasympathetic tone (reversed by atropine but not propranolol); Kv1.1 is expressed in juxtaparanodes of the vagus nerve, suggesting it regulates parasympathetic outflow to the heart\",\n      \"method\": \"Simultaneous video EEG-ECG recordings; selective autonomic pharmacological blockade (atropine/propranolol); immunohistochemistry of vagus nerve; cardiac structural analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO model with pharmacological dissection of autonomic mechanism and localization evidence\",\n      \"pmids\": [\"20392939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NRG1 acting through ErbB4 increases intrinsic excitability of fast-spiking parvalbumin interneurons by increasing near-threshold responsiveness and decreasing action potential voltage threshold through Kv1.1\",\n      \"method\": \"Whole-cell patch clamp in ErbB4 conditional knockout mice; pharmacological manipulation of Kv1.1; seizure susceptibility models\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological dissection with defined cellular and behavioral readouts\",\n      \"pmids\": [\"22158511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"mTOR-dependent regulation of Kv1.1 mRNA translation in dendrites involves two opposing mechanisms: when mTORC1 is active, miR-129 represses Kv1.1 mRNA translation; when mTORC1 is inhibited, degradation of high-affinity HuD target mRNAs frees HuD to bind and promote Kv1.1 mRNA translation\",\n      \"method\": \"miRNA identification; HuD RNA-binding protein binding assays; mTOR inhibition studies; polysome profiling; reporter assays in neurons\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mechanistic dissection of competing translational regulators with multiple orthogonal methods\",\n      \"pmids\": [\"23836929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Kv1.1 acts as a mechanosensitive brake in sensory neurons: mechanosensitivity is attributed to Kv1.1 subunits in Kv1.1-Kv1.2 heteromers through facilitation of voltage-dependent open probability; IKmech expression in C-HTMRs opposes slow MS cation currents, setting mechanical firing threshold; Kv1.1 dominant negative or inhibition causes mechanical allodynia without heat hyperalgesia\",\n      \"method\": \"Toxin profiling; transgenic mouse studies; patch clamp of DRG neurons; Kv1.1 dominant negative expression; behavioral assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — convergent genetic and pharmacological evidence with behavioral phenotype\",\n      \"pmids\": [\"23473320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss of Kv1.1 in Kcna1-null hippocampus increases presynaptic neurotransmitter release at mossy fiber and perforant path terminals (reduced paired-pulse ratios, enhanced postsynaptic responses), which reduces spike timing reliability of CA3 principal cells and promotes pathological high-frequency oscillations\",\n      \"method\": \"Multielectrode array extracellular recordings; micro-dissection experiments; DTX-κ pharmacology in wild-type slices\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO model with pharmacological validation and circuit dissection\",\n      \"pmids\": [\"23466697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KCNA1 expression is induced by oncogenic stress, and Kv1.1 relocates from cytoplasm to plasma membrane upon loss of PKA-dependent phosphorylation at S446; membrane-localized Kv1.1 changes membrane potential and triggers cellular senescence; phosphomimetic S446 mutant maintains cytoplasmic localization and allows OIS escape\",\n      \"method\": \"Loss-of-function genetic screen; subcellular fractionation; mutagenesis of S446; membrane potential measurements; transformation assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic screen validated with mutagenesis and functional assays in single lab\",\n      \"pmids\": [\"23774215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"KCNE4 β-subunit exerts a drastic inhibitory effect specifically on Kv1.1 and Kv1.3 homomeric currents and on Kv1.1/Kv1.2 and Kv1.2/Kv1.3 heteromeric currents but not on Kv1.2, Kv1.4, Kv1.5, or Kv4.3; Kv1.1 and KCNE4 colocalize at the cell surface\",\n      \"method\": \"Heterologous expression in Xenopus oocytes and HEK293 cells; electrophysiology; confocal microscopy; Western blot\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic channel specificity testing in two expression systems with localization\",\n      \"pmids\": [\"12944270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Kv1.1 (V408A/+) knock-in mice exhibit spontaneous myokymic discharges originating from motor nerve axons independent of neuromuscular junction; the V408A mutation causes abnormal spontaneous Ca2+ signals in motor nerve axons; fatigue, ischemia, and low temperature exacerbate myokymic activity\",\n      \"method\": \"In vivo nerve-muscle preparations; two-photon laser scanning microscopy of Ca2+ signals; nerve axotomy experiments; EMG recordings\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knock-in mouse model with two-photon imaging and axotomy dissecting site of origin\",\n      \"pmids\": [\"22609489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Following kainic-acid induced status epilepticus, Kv1.1 expression is suppressed in two phases: (1) initial mTOR-dependent suppression (reversed by rapamycin) followed by (2) persistent miR-129-5p-mediated translational repression independent of mTOR; reduced Kv1.1 in CA1 pyramidal neurons lowers action potential firing threshold\",\n      \"method\": \"Kainic acid TLE model; rapamycin treatment; miR-129-5p quantification; patch clamp recordings from CA1 neurons\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two distinct mechanistic phases identified with pharmacology, miRNA measurements, and electrophysiology\",\n      \"pmids\": [\"25270294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Pharmacological or genetic deletion of Kv1.1 broadens presynaptic spike width; an EA1 heterozygous dominant Kv1.1 mutation (V408A) similarly broadens basal presynaptic spike shape but, unlike deletion, abolishes spike width modulation by subthreshold somatic depolarization, suggesting disruption of normal presynaptic Kv1 channel stoichiometry\",\n      \"method\": \"Scanning ion conductance microscopy to record from intact small synaptic boutons; pharmacological Kv1.1 blockade; heterozygous Kv1.1 V408A knock-in mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — novel recording method from intact boutons with parallel pharmacological and genetic approaches\",\n      \"pmids\": [\"28193892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Patient-derived LGI1 antibodies disrupt LGI1 interaction with ADAM23 (presynaptic) and ADAM22 (postsynaptic), causing decreased synaptic Kv1.1 levels before AMPA receptor reduction, leading to neuronal hyperexcitability, increased presynaptic glutamate release, and impaired LTP\",\n      \"method\": \"Patient IgG cerebroventricular transfer in mice; confocal analysis of hippocampal slices; patch clamp of dentate gyrus and CA1 neurons; field potential LTP recordings\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — patient antibody model with electrophysiology showing Kv1.1 reduction precedes AMPA receptor loss\",\n      \"pmids\": [\"30346486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Neuron-specific deletion of Kcna1 (using Synapsin1-Cre) is sufficient to cause epilepsy, premature death, and cardiorespiratory dysregulation, demonstrating that brain-driven (not cardiac-intrinsic) Kv1.1 deficiency underlies SUDEP risk; residual Kv1.1 in cerebellum (where Synapsin1-Cre is less active) may modulate ictal cardiorespiratory dysfunction\",\n      \"method\": \"Conditional knockout (floxed Kcna1 × Synapsin1-Cre); EEG, ECG, plethysmography; survival analysis; heart rate variability analysis\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with multimodal physiological recording establishing neuron-specific mechanism\",\n      \"pmids\": [\"31978607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RNA editing of Kv1.1 at position I400V (Ile→Val) in the S6 segment generates 4-aminopyridine-insensitive channels; editing ratio is increased ~4-fold in the entorhinal cortex of chronic epileptic rats, reducing ictogenic potential of 4-AP\",\n      \"method\": \"Sequencing of RNA editing in kainic acid model; electrophysiology of I400V channels in Xenopus oocytes\",\n      \"journal\": \"Epilepsia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional validation of editing site in oocytes correlated with in vivo editing measurements\",\n      \"pmids\": [\"21371023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KCNA1 L319R mutation accelerates protein degradation via the proteasome pathway and disrupts Kv1.1 membrane expression; both L319R and N255K mutations reduce K+ currents with altered gating and dominant negative effect, causing familial paroxysmal kinesigenic dyskinesia\",\n      \"method\": \"Whole-exome sequencing; proteasome inhibitor experiments; patch clamp in HEK293 cells; dominant-negative co-expression\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical degradation assay plus electrophysiology in single lab\",\n      \"pmids\": [\"29294000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Kv1.1 deletion augments carotid body chemosensory discharge during hypoxia and increases frequency of spontaneous and miniature EPSCs in nucleus tractus solitarius neurons, demonstrating Kv1.1 regulates afferent hypoxic chemosensory pathway and respiratory control\",\n      \"method\": \"Plethysmography; in vitro carotid body sensory discharge recordings; whole-cell patch clamp of NTS neurons in brainstem slices; immunohistochemistry\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO model with in vitro and in vivo recordings across multiple levels of chemosensory pathway\",\n      \"pmids\": [\"15800194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mu opioid receptor activation inhibits GABAergic inputs to basolateral amygdala neurons through presynaptic Kv1.1/1.2 channels; selective Kv1.1 blocker (DTX-K) abolishes DAMGO's inhibitory effect on mIPSCs; Kv1.1 and Kv1.2 colocalize with synaptophysin in BLA\",\n      \"method\": \"Whole-cell voltage clamp with selective toxin blockers (DTX-K for Kv1.1, tityustoxin-Kα for Kv1.2); double immunofluorescence with synaptophysin\",\n      \"journal\": \"Journal of neurophysiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological specificity supported by colocalization; single lab\",\n      \"pmids\": [\"16306173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Nitric oxide increases GABAergic mIPSC frequency to PVN presympathetic neurons through cGMP/PKG signaling acting downstream on presynaptic Kv1.1/1.2 channels; selective blockade of Kv1.1 (DTX-K) or Kv1.2 abolishes NO-induced potentiation of GABA release\",\n      \"method\": \"Whole-cell patch clamp in PVN brain slices; selective Kv channel blockers; 8-Br-cADPR controls; immunofluorescence for Kv1.1/Kv1.2 and synaptophysin\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pharmacological pathway placement with colocalization; single lab\",\n      \"pmids\": [\"17869444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Kv1.1 and Kv1.3 channels contribute to RGC degeneration after optic nerve transection through different apoptotic pathways: Kv1.1 siRNA knockdown increases antiapoptotic Bcl-XL, while Kv1.3 siRNA reduces proapoptotic caspase-3, caspase-9, and Bad\",\n      \"method\": \"siRNA knockdown via intraocular injection with retrograde transport to RGCs; quantitative RT-PCR; immunohistochemistry; cell death counting\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — channel-specific siRNAs with defined apoptotic marker readouts\",\n      \"pmids\": [\"19696788\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KCNA1-encoded Kv1.1 is a voltage-gated delayed-rectifier K+ channel subunit that forms homo- and heterotetramers (with Kv1.2, Kv1.4, Kv1.6, and Kvβ subunits) targeted to axonal juxtaparanodes, presynaptic terminals, and dendrites, where it dampens neuronal excitability by setting action potential threshold, controlling firing precision and spike width; its activity is regulated by palmitoylation at C243 (voltage sensing), PKA-driven phosphorylation and membrane translocation, arachidonic acid via Ca2+-independent PLA2, mTOR- and miR-129-dependent translational control of dendritic mRNA, and Kvβ1 aldoketoreductase-dependent cofactor oxidation; loss-of-function mutations or deficiency cause episodic ataxia type 1, seizures, myokymia, hypomagnesemia, and SUDEP through enhanced neuronal excitability and, in the brain, aberrant parasympathetic outflow to the heart.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KCNA1 encodes the voltage-gated potassium channel subunit Kv1.1, a delayed-rectifier that assembles into homo- and heterotetramers with other Shaker-family subunits (Kv1.2, Kv1.4) and accessory Kvβ subunits to dampen neuronal excitability, control action potential threshold and width, and ensure temporal precision of firing across sensory, motor, and autonomic circuits [PMID:8046438, PMID:12611922, PMID:14534254, PMID:28193892]. Channel gating is tuned by palmitoylation at C243 (modulating voltage sensing), sialic acid glycosylation, Kvβ1 aldoketoreductase-dependent cofactor oxidation, PKA-driven membrane translocation, and mTOR/miR-129-mediated translational control of dendritic Kv1.1 mRNA [PMID:15837928, PMID:8702582, PMID:18222921, PMID:12681381, PMID:23836929]. Loss-of-function mutations cause episodic ataxia type 1 with myokymia through dominant-negative or haploinsufficiency mechanisms, and certain mutations cause autosomal dominant hypomagnesemia by disrupting the membrane potential required for TRPM6-dependent Mg²⁺ reabsorption in the distal convoluted tubule [PMID:7842011, PMID:9526001, PMID:19307729]. Neuron-specific Kv1.1 deficiency is sufficient to produce seizures and sudden unexpected death in epilepsy (SUDEP) through brain-driven cardiorespiratory dysregulation involving excessive parasympathetic outflow via the vagus nerve [PMID:20392939, PMID:31978607].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing that KCNA1 is the disease gene for episodic ataxia type 1 linked loss-of-function K⁺ channel mutations to a defined human neurological disorder.\",\n      \"evidence\": \"Mutation analysis of KCNA1 coding region across EA1 families with heterologous expression confirming functional deficits\",\n      \"pmids\": [\"7842011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise mechanism of dominant-negative vs. haploinsufficiency for each mutation not yet resolved\", \"No structural model explaining mutation-specific gating defects\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Mapping Kv1.1 protein to synaptic terminals, juxtaparanodes, and dendrites defined the subcellular compartments where the channel regulates excitability.\",\n      \"evidence\": \"Isoform-specific immunocytochemistry in mouse brain\",\n      \"pmids\": [\"8046438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each subcellular pool to specific physiological functions not determined\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Demonstrating cotranslational assembly of Kv1.1 exclusively with other Shaker-family subunits established the rules governing channel heteromerization.\",\n      \"evidence\": \"Co-immunoprecipitation from in vitro translations and transfected cells; pulse-chase metabolic labeling; glycosylation site mutagenesis\",\n      \"pmids\": [\"8126562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of heteromeric complexes in native tissue not determined\", \"Assembly chaperone requirements unknown\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identifying arachidonic acid released by Ca²⁺-independent PLA2 as a modulator of Kv1.1 gating kinetics revealed a lipid-signaling regulatory axis.\",\n      \"evidence\": \"Intracellular PLA2 and exogenous arachidonic acid application with mechanism-based inhibitors; whole-cell patch clamp in Sf9 cells\",\n      \"pmids\": [\"7852365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding site on Kv1.1 for arachidonic acid not identified\", \"In vivo relevance not established\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Showing that sialic acid glycosylation modulates voltage dependence of activation by altering the local electric field linked post-translational glycan processing to channel biophysics.\",\n      \"evidence\": \"Expression in glycosylation-deficient CHO Lec mutant cells; sialidase treatment; electrophysiology\",\n      \"pmids\": [\"8702582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo glycosylation heterogeneity at Kv1.1 not characterized\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Systematic analysis of EA1 mutations separated two mechanistic classes—dominant-negative effects on heteromeric channels versus haploinsufficiency from protein instability—explaining clinical variability.\",\n      \"evidence\": \"TEA-tagging strategy in Xenopus oocytes to discriminate subunit contributions; Western blot quantification\",\n      \"pmids\": [\"9526001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype correlation across all known EA1 mutations incomplete\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Kcna1-null mice revealed Kv1.1 as a regulator of pain processing, with knockout causing hyperalgesia and blunted morphine antinociception.\",\n      \"evidence\": \"Behavioral pain assays (paw flick, hot plate, formalin) in Kcna1-null vs. wild-type mice\",\n      \"pmids\": [\"9718989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific DRG neuron subtypes mediating Kv1.1-dependent nociception not identified at this time\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Quantitative electrophysiology in Kcna1-null brainstem slices and in vivo recordings established that Kv1.1 supplies ~50% of low-threshold K⁺ current in auditory neurons and is essential for temporal precision of spike initiation.\",\n      \"evidence\": \"Patch clamp in MNTB slices from Kcna1-null mice; DTX pharmacology; in vivo single-unit recordings from VCN and MNTB\",\n      \"pmids\": [\"12611922\", \"14534254\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of compensatory Kv1.2/Kv1.6 contribution quantified only indirectly via DTX sensitivity\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"PKA phosphorylation was shown to drive rapid Kv1.1 translocation to the plasma membrane, increasing current and altering voltage dependence, while PKC acted indirectly through protein synthesis.\",\n      \"evidence\": \"Patch clamp in stably transfected HEK293 cells with PKA/PKC activators; phosphorylation assays\",\n      \"pmids\": [\"12681381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific PKA phosphorylation site(s) not mapped in this study\", \"In vivo confirmation of PKA-dependent trafficking lacking\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The mceph mouse truncation and KCNE4 β-subunit studies revealed additional mechanisms of Kv1.1 suppression—dominant-negative sequestration of partner subunits and β-subunit-mediated current inhibition, respectively.\",\n      \"evidence\": \"Positional cloning with immunoblot showing reduced Kv1.2/Kv1.3 in mceph hippocampus; heterologous KCNE4 co-expression in oocytes and HEK293 cells\",\n      \"pmids\": [\"14686897\", \"12944270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"KCNE4-Kv1.1 stoichiometry and binding interface unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying palmitoylation at C243 as a modulator of voltage sensing (20 mV shift in I-V curve) linked a reversible lipid modification to the biophysics of Kv1.1 gating.\",\n      \"evidence\": \"[³H]palmitate radiolabeling; C243 mutagenesis; whole-cell patch clamp in Sf9 cells\",\n      \"pmids\": [\"15837928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Palmitoyl acyltransferase responsible not identified\", \"Dynamic regulation of palmitoylation state in neurons not characterized\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Kv1.1 was placed in the afferent hypoxic chemosensory pathway: its deletion augmented carotid body discharge and excitatory transmission in NTS, linking Kv1.1 to respiratory control.\",\n      \"evidence\": \"Plethysmography; in vitro carotid body recordings; patch clamp of NTS neurons in Kcna1-null mice\",\n      \"pmids\": [\"15800194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific Kv1.1-containing heteromer subtypes in carotid body not identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Discovery that mTOR suppresses dendritic Kv1.1 translation introduced activity-dependent local synthesis as a mechanism for regulating dendritic excitability independently of axonal Kv1.1.\",\n      \"evidence\": \"Photoconvertible Kaede-Kv1.1 reporter for local synthesis; rapamycin treatment; surface biotinylation in hippocampal neurons\",\n      \"pmids\": [\"17023663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cis-regulatory elements in Kv1.1 mRNA mediating dendritic targeting not mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that Kvβ1 functions as an aldoketoreductase whose cofactor oxidation state controls Kv1.1 open-channel current linked cellular metabolic status to K⁺ channel conductance.\",\n      \"evidence\": \"In vitro enzymatic assay for Kvβ1; NADP⁺/H₂O₂ application during patch clamp; catalytic site mutagenesis\",\n      \"pmids\": [\"18222921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates of Kvβ1 reductase in neurons not identified\", \"In vivo metabolic conditions that trigger redox switching unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"A KCNA1 N255D mutation causing autosomal dominant hypomagnesemia established a renal role for Kv1.1, showing it sets the membrane potential required for TRPM6-mediated Mg²⁺ reabsorption in the distal convoluted tubule.\",\n      \"evidence\": \"Positional cloning; immunolocalization in kidney; patch clamp showing dominant-negative loss of function\",\n      \"pmids\": [\"19307729\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kv1.1 heteromer composition in DCT not determined\", \"Mechanism by which membrane potential specifically couples to TRPM6 activity not fully resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Kcna1-null mice showed brain-driven cardiac arrhythmias reversed by atropine, identifying excessive parasympathetic outflow via Kv1.1-expressing vagus nerve juxtaparanodes as the mechanism linking Kv1.1 loss to cardiac dysfunction.\",\n      \"evidence\": \"Simultaneous video-EEG-ECG; selective autonomic blockade; vagus nerve immunohistochemistry\",\n      \"pmids\": [\"20392939\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cardiac arrhythmias are purely ictal or also interictal not fully resolved\", \"Role of respiratory dysfunction in SUDEP mechanism not dissected\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"RNA editing at I400V in the S6 segment was found to generate 4-AP-insensitive Kv1.1 channels, with editing upregulated in chronic epilepsy, suggesting an endogenous compensatory response to hyperexcitability.\",\n      \"evidence\": \"RNA editing quantification in kainic acid epilepsy model; electrophysiology of I400V channels in Xenopus oocytes\",\n      \"pmids\": [\"21371023\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ADAR enzyme responsible for I400V editing not identified\", \"Functional impact of altered editing on seizure frequency not tested in vivo\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"V408A knock-in mice demonstrated that EA1 myokymia originates from spontaneous Ca²⁺ signals in motor nerve axons, independent of the neuromuscular junction, placing the pathogenic mechanism in the axon itself.\",\n      \"evidence\": \"In vivo nerve-muscle preparation; two-photon Ca²⁺ imaging; nerve axotomy experiments\",\n      \"pmids\": [\"22609489\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of aberrant Ca²⁺ entry in V408A axons not determined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Kv1.1 was identified as a mechanosensitive brake in C-fiber high-threshold mechanoreceptors: Kv1.1 in Kv1.1-Kv1.2 heteromers opposes slow MS cation currents to set mechanical firing threshold.\",\n      \"evidence\": \"Toxin profiling; transgenic mouse studies; DRG neuron patch clamp; behavioral mechanical allodynia assays\",\n      \"pmids\": [\"23473320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for mechanosensitivity of Kv1.1-containing heteromers unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two competing translational regulators—miR-129 (repressor) and HuD (activator)—were shown to mediate mTOR-dependent control of dendritic Kv1.1 synthesis, refining the mechanism by which neuronal activity tunes local Kv1.1 levels.\",\n      \"evidence\": \"miRNA identification; HuD RNA-binding assays; polysome profiling; reporter assays in neurons\",\n      \"pmids\": [\"23836929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether miR-129 and HuD binding sites overlap or are distinct on Kv1.1 3′-UTR not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Loss of Kv1.1 in hippocampus increased presynaptic neurotransmitter release at mossy fiber and perforant path terminals, linking presynaptic Kv1.1 to circuit-level timing and pathological oscillations.\",\n      \"evidence\": \"Multielectrode array recordings in Kcna1-null hippocampal slices; DTX-κ pharmacology\",\n      \"pmids\": [\"23466697\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether increased release is purely due to spike broadening or also involves resting Ca²⁺ changes not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Direct recording from small synaptic boutons showed that Kv1.1 controls basal presynaptic spike width, and that EA1 V408A heterozygosity abolishes analog modulation of spike width by somatic depolarization, revealing a novel disease mechanism.\",\n      \"evidence\": \"Scanning ion conductance microscopy of intact boutons; DTX-K; heterozygous V408A knock-in mice\",\n      \"pmids\": [\"28193892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subunit stoichiometry of native presynaptic Kv1 channels disrupted by V408A not directly measured\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"LGI1 autoantibodies were shown to reduce synaptic Kv1.1 levels before AMPA receptors, establishing Kv1.1 displacement from the LGI1-ADAM22/23 complex as an early driver of autoimmune neuronal hyperexcitability.\",\n      \"evidence\": \"Patient IgG cerebroventricular transfer in mice; confocal quantification; patch clamp and LTP recordings\",\n      \"pmids\": [\"30346486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Kv1.1 removal from synaptic membrane (internalization vs. lateral diffusion) not determined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Neuron-specific conditional deletion proved that brain Kv1.1 loss—not cardiac-intrinsic deficiency—is sufficient for epilepsy and SUDEP-like cardiorespiratory failure, resolving the tissue origin of SUDEP risk.\",\n      \"evidence\": \"Floxed Kcna1 × Synapsin1-Cre conditional KO; EEG, ECG, plethysmography; survival analysis\",\n      \"pmids\": [\"31978607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific brain circuits (brainstem vs. cortical) driving fatal cardiorespiratory collapse not dissected\", \"Whether cerebellar Kv1.1 retention modulates SUDEP threshold confirmed only indirectly\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the high-resolution structural basis for EA1 mutation-specific gating defects, the identity and regulation of the palmitoyl acyltransferase(s) and ADAR(s) acting on Kv1.1, the precise subunit stoichiometry of native Kv1.1-containing heteromers at defined synapses, and the specific brainstem circuits through which Kv1.1 loss drives fatal cardiorespiratory arrest.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No cryo-EM or X-ray structure of human Kv1.1 homomeric or heteromeric channel\", \"Palmitoyl acyltransferase identity unknown\", \"Circuit-level mechanism of SUDEP not resolved at cell-type specificity\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 3, 5, 8, 13, 14, 17, 25]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [29]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 17, 19, 24, 31]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [22, 31]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [14, 18, 20, 26, 27, 30, 37]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 5, 8, 24, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [19, 28, 34]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 5, 10, 24, 39]}\n    ],\n    \"complexes\": [\n      \"Kv1.1-Kv1.2 heterotetramer\",\n      \"Kv1.1-Kv1.4 heterotetramer\",\n      \"Kv1.1/Kvβ1 complex\"\n    ],\n    \"partners\": [\n      \"KCNA2\",\n      \"KCNA4\",\n      \"KCNAB1\",\n      \"KCNE4\",\n      \"LGI1\",\n      \"ADAM22\",\n      \"ADAM23\",\n      \"TRPM6\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}