{"gene":"KCNA1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1994,"finding":"Kv1.1 forms functional homomultimeric channels when expressed in mammalian cell lines, producing a delayed-rectifier type K+ current sensitive to dendrotoxin, charybdotoxin, and other pharmacological agents. Biophysical characterization showed it resembles the K+ channel in C6 glioma cells and astrocytes.","method":"Stable expression in mammalian cell lines, whole-cell patch clamp, pharmacological profiling","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct electrophysiological reconstitution in mammalian cells with pharmacological characterization, widely replicated","pmids":["7517498"],"is_preprint":false},{"year":1994,"finding":"Kv1.1 protein is localized to synaptic terminals, somata, juxta-paranodal regions of myelinated axons, unmyelinated axons, specialized junctions among axons, and proximal dendrites in the mouse brain, with region-specific distribution distinct from Kv1.2.","method":"Immunocytochemistry in mouse brain sections","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct immunolocalization replicated across multiple brain regions and labs","pmids":["8046438"],"is_preprint":false},{"year":1994,"finding":"Kv1.1 assembles cotranslationally with other Shaker-like subunits (Kv1.4) but not with non-Shaker Kv2.1; N207 glycosylation occurs but is not required for subunit assembly, surface transport, or function; surface channels exist as two species (~57 and ~59 kDa) with precursor-product relationship.","method":"Immune purification of in vitro translations and transfected mouse L-cells, pulse-chase metabolic labeling, site-directed mutagenesis of glycosylation site, SDS-PAGE","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution, mutagenesis, and pulse-chase labeling in single rigorous study","pmids":["8126562"],"is_preprint":false},{"year":1995,"finding":"Ca2+-independent phospholipase A2 (iPLA2) modulates Kv1.1 channel kinetics by releasing arachidonic acid, which accelerates both activation and induces inactivation of the channel. The effect is arachidonic-acid specific and independent of eicosanoid metabolites.","method":"Whole-cell patch clamp of Sf9 cells expressing human Kv1.1, intracellular administration of iPLA2, mechanism-based inhibitor, exogenous fatty acid application","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution in Sf9 cells with multiple controls, mechanism-based inhibitor, and fatty acid specificity tests","pmids":["7852365"],"is_preprint":false},{"year":1996,"finding":"Sialic acid residues on Kv1.1 modulate its voltage dependence of activation (shifting V1/2 to more positive voltages when sialidation is prevented) and slow activation kinetics; sialic acids act as negative surface charges that influence the local electric field at the voltage sensor. Glycosylation is not required for cell surface expression.","method":"Expression of Kv1.1 in glycosylation-deficient CHO Lec mutant cell lines, whole-cell patch clamp, sialidase treatment, Ca2+ application","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — functional reconstitution with glycosylation-deficient cell lines and enzyme treatment, multiple orthogonal methods","pmids":["8702582"],"is_preprint":false},{"year":1997,"finding":"Antisense oligonucleotide-mediated knockdown of Kv1.1 in hippocampal neurons reduces late-rectifying K+ current in dentate granule cells and impairs associative memory (passive avoidance and spatial memory tasks) in mice and rats, demonstrating Kv1.1 is required for hippocampus-dependent memory formation.","method":"Intracerebroventricular antisense oligonucleotide injection, whole-cell patch clamp of dentate granule cells, behavioral testing (passive avoidance, Morris water maze)","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antisense knockdown with electrophysiological and behavioral readouts in two species, single lab","pmids":["9114006"],"is_preprint":false},{"year":1997,"finding":"Truncated Kv1.1 (Kv1.1N206Tag) forms heteromultimeric complexes with native Kv1.4 and Kv1.5 channels and traps these complexes in the endoplasmic reticulum, preventing surface expression — establishing a dominant-negative mechanism via ER retention.","method":"Transient expression in GH3 cells, double immunoprecipitation, subcellular fractionation, immunofluorescence/confocal microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — Co-IP, subcellular fractionation, and confocal colocalization in single study","pmids":["9334228"],"is_preprint":false},{"year":1998,"finding":"Episodic ataxia type 1 (EA1) mutations in Kv1.1 affect channel function by two mechanisms: dominant negative effects (most mutations), or haploinsufficiency (R239S and F249I, which show reduced protein levels). EA subunits coassemble with wild-type subunits in mixed stoichiometries. Channels bearing EA mutations show lower current amplitudes and altered gating.","method":"Expression of EA mutant cRNAs in Xenopus oocytes, co-injection experiments, TEA-tagging to discriminate subunit contribution, Western blot","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — functional reconstitution with mutagenesis, pharmacological subunit discrimination, and protein quantification","pmids":["9526001"],"is_preprint":false},{"year":1998,"finding":"Kv1.1 loss-of-function (Kcna1 knockout) causes thermal hyperalgesia and increased formalin-induced nociception, and blunts morphine-induced antinociception, establishing Kv1.1 as a regulator of nociceptive and antinociceptive signaling.","method":"Kcna1 knockout mice, paw flick assay, hot plate assay, formalin test, morphine antinociception assay","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with multiple behavioral nociceptive readouts, single lab","pmids":["9718989"],"is_preprint":false},{"year":1999,"finding":"EA1 mutations V408A and E325D in Kv1.1, when co-assembled with Kv1.2 using tandem-linked subunits, produce heteromeric channels with altered kinetics of activation, deactivation, C-type inactivation, and voltage dependence. V408A reduces mean open duration ~3-fold in single-channel analysis, destabilizing the open state of both homomeric and heteromeric channels.","method":"Tandemly linked subunit expression in Xenopus oocytes, single-channel patch clamp, macroscopic current analysis","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — single-channel reconstitution with tandem subunits and multiple gating parameter analyses","pmids":["10428758"],"is_preprint":false},{"year":1999,"finding":"Protein kinase C (PKC) activation inhibits Kv1.1 current by up to 90% via a mechanism requiring a C3 exoenzyme substrate (Rho GTPase pathway), without altering activation gating or reducing membrane channel protein. Direct phosphorylation of Kv1.1 by PKC was not responsible.","method":"Xenopus oocyte expression, phorbol ester treatment, PKC inhibitors, site-directed mutagenesis of PKC phosphorylation sites, Western blot, botulinum toxin C3 injection","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis of phosphorylation sites combined with toxin-based pathway dissection, single lab","pmids":["10409113"],"is_preprint":false},{"year":1999,"finding":"Dendrotoxin K (DTXk) selectively inhibits Kv1.1-containing channels; its K3 residue in the 310-helical N-terminal region is critical for Kv1.1 recognition (K3A mutation causes ~1246-fold loss of potency), while W25 and K26 in the beta-turn are also important for toxin-channel interaction.","method":"Site-directed mutagenesis of DTXk, radioligand binding competition assay with [125I]DTXk and [125I]alphaDTX to rat brain membranes, two-electrode voltage clamp in Xenopus oocytes expressing Kv1.1","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with binding and functional assays, identifies specific interaction residues","pmids":["10429207"],"is_preprint":false},{"year":1999,"finding":"G protein beta-gamma (Gbeta1gamma2) subunits directly interact with Kv1.1 and Kvbeta1.1, promote co-assembly of more Kvbeta1.1 with Kv1.1, and increase the extent of N-type (A-type) inactivation of Kv1.1/Kvbeta1.1 channels. This effect is occluded by microfilament disruption and requires co-expression during channel assembly rather than acute application.","method":"Xenopus oocyte co-expression, GST pulldown of Gbeta1gamma2 with Kv1.1/Kvbeta1.1 fusion fragments, co-immunoprecipitation, electrophysiology, C-terminal betaARK fragment scavenging","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — GST pulldown, Co-IP, and functional electrophysiology in single study","pmids":["10064591"],"is_preprint":false},{"year":1999,"finding":"The R417stop truncation mutation in Kv1.1 (EA1) impairs both tetramerization with wild-type subunits and membrane targeting of heterotetramers, trapping channels intracellularly. Other EA1 mutations (V404I, P244H) do not affect tetramerization or trafficking but alter channel kinetics.","method":"Xenopus oocyte expression, electrophysiology, pharmacological subunit discrimination, confocal laser scanning microscopy of EGFP-tagged subunits","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — functional electrophysiology, pharmacological discrimination, and GFP-based trafficking imaging in one study","pmids":["11773313"],"is_preprint":false},{"year":2001,"finding":"EA1 nonsense mutations in Kv1.1 cause intracellular aggregation and detergent insolubility of the mutant protein, which can be transferred to co-assembled Kv1 alpha- and Kvbeta-subunits. EA1 missense mutations, in contrast, do not alter folding or trafficking compared to wild-type.","method":"Heterologous expression, detergent solubility assay, immunostaining, co-assembly analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods in single lab study","pmids":["11679591"],"is_preprint":false},{"year":2003,"finding":"Kv1.1 subunits contribute ~50% of the low voltage-activated potassium current (IKL) in auditory MNTB neurons. Kcna1 knockout mice show approximately halved IKL amplitude, doubled action potential firing, and halved rheobase. Residual IKL in knockout neurons is carried by Kv1.2/Kv1.6-containing channels (DTX-sensitive).","method":"Whole-cell patch clamp in brainstem slices from Kcna1-null mice and wild-type littermates, dendrotoxin pharmacology","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout combined with pharmacology and electrophysiology, replicated across genotypes","pmids":["12611922"],"is_preprint":false},{"year":2003,"finding":"Kv1.1 glycosylation (N-linked, at S1-S2 linker) does not affect protein stability, cellular localization, or trafficking to the cell surface, in contrast to Kv1.4. A pore region determinant in Kv1.1 vs Kv1.4 dictates whether glycosylation influences trafficking.","method":"Prevention of N-glycosylation (tunicamycin, mutagenesis), Western blot for protein stability, immunocytochemistry for cellular localization, chimeric channel construction","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis and chimeric channels with protein stability and trafficking assays","pmids":["14688283"],"is_preprint":false},{"year":2003,"finding":"Kv1.1 is expressed in the medial nucleus of the trapezoid body (MNTB) and is required for temporal precision (low jitter) in auditory signal processing in vivo; Kcna1-null mice show increased first-spike latency jitter in VCN and MNTB neurons and failure to follow high-frequency amplitude-modulated stimuli.","method":"In vivo single-unit recordings from VCN and MNTB neurons of Kcna1-null and wild-type mice during auditory stimulation","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo electrophysiology in genetic knockout, replicated across multiple auditory nuclei","pmids":["14534254"],"is_preprint":false},{"year":2003,"finding":"Truncation of Kv1.1 at amino acid 230 (mceph mutation, 11-bp deletion) in mice causes megencephaly; the truncated protein lacks C-terminal domains, and sequestration of Kv1.2 and Kv1.3 proteins is observed (reduced protein levels despite normal mRNA), suggesting dominant interaction at the protein level. Seizures occur in these mice.","method":"Positional cloning, sequencing, immunoblot for Kv1.2/Kv1.3 protein levels, in situ hybridization for mRNA, EEG","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic model with protein-level analysis, single lab","pmids":["14686897"],"is_preprint":false},{"year":2005,"finding":"Human Kv1.1 is palmitoylated at cysteine C243 in the cytosolic S2-S3 linker domain; preventing palmitoylation at C243 by mutagenesis causes a 20-mV leftward shift in the current-voltage relationship, implicating palmitoylation at C243 in modulating voltage sensing through protein-membrane interactions.","method":"Heterologous expression in Sf9 cells, [3H]palmitate radiolabeling, chemical stability studies, site-directed mutagenesis, whole-cell patch clamp","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — covalent radiolabeling, mutagenesis, and functional electrophysiology in single rigorous study","pmids":["15837928"],"is_preprint":false},{"year":2006,"finding":"Kv1.1-containing channels (identified by dendrotoxin-K) underlie low-threshold K+ current (Ikl) in MNTB neurons and are critical for temporal precision of spike initiation; partial (~50%) reduction of Ikl by 3 nM DTX-K or Kcna1 knockout similarly increases AP jitter and latency, especially at high stimulation rates.","method":"Whole-cell patch clamp in mouse brain slices, selective DTX-K pharmacology at multiple concentrations, comparison with Kcna1-/- mice","journal":"Journal of neurophysiology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — pharmacology and genetics converge on same phenotype, multiple concentrations tested","pmids":["16672305"],"is_preprint":false},{"year":2006,"finding":"mTOR activity suppresses Kv1.1 mRNA translation in dendrites; inhibition of mTOR with rapamycin or of NMDA receptors increases Kv1.1 protein in hippocampal neuron dendrites (but not axons). Local dendritic synthesis of Kv1.1 was demonstrated using a Kaede photoconvertible reporter.","method":"Rapamycin treatment of hippocampal neurons, Kv1.1-Kaede reporter for local protein synthesis, immunostaining, NMDA receptor blockade","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — live-cell reporter for local synthesis, pharmacological manipulation, compartment-specific protein quantification","pmids":["17023663"],"is_preprint":false},{"year":2006,"finding":"EA1 mutations E325D, V404I, V408A, and I177N in Kv1.1 alter N-type inactivation properties of heteromeric Kv1.4-1.1 channels co-assembled with Kvbeta1.1 or Kvbeta1.2: they decrease the rate and degree of N-type inactivation, accelerate recovery from fast inactivation, and shift steady-state inactivation voltage dependence.","method":"Expression of tandemly linked Kv1.4-1.1 constructs with EA1 mutations in Xenopus oocytes, two-electrode voltage clamp","journal":"The European journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — tandem-linked subunit reconstitution with systematic mutagenesis and multiple gating analyses","pmids":["17156368"],"is_preprint":false},{"year":2008,"finding":"Kvbeta1 is a functional aldoketoreductase; oxidation of the NADPH cofactor bound to Kvbeta1 (either enzymatically by a substrate or non-enzymatically by H2O2 or NADP+) causes a large increase in open Kv1.1 channel current. This cofactor oxidation rate is ~2-fold faster at 0 mV than at -100 mV, indicating that Kv1.1 voltage-dependent conformational changes regulate Kvbeta1 enzymatic activity.","method":"Patch clamp of Kv1.1 + Kvbeta1 expressed in oocytes, substrate addition, H2O2/NADP+ treatment, deletion mutagenesis of Kv1.1 C-terminus","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic and functional reconstitution with multiple reagents and mutagenesis","pmids":["18222921"],"is_preprint":false},{"year":2009,"finding":"A missense mutation N255D in KCNA1 (S3 transmembrane segment) causes autosomal dominant hypomagnesemia by creating a non-functional channel with dominant negative effect on wild-type Kv1.1. Kv1.1 is expressed in the kidney distal convoluted tubule (DCT) where it colocalizes with the Mg2+ transporter TRPM6 on the luminal membrane, establishing a favorable membrane potential for TRPM6-mediated Mg2+ reabsorption.","method":"Positional cloning, patch clamp of N255D-expressing HEK cells, co-expression with wild-type, immunohistochemistry of kidney sections for Kv1.1/TRPM6 colocalization","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — patch clamp, dominant-negative testing, and immunohistochemical colocalization in kidney, single rigorous study","pmids":["19307729"],"is_preprint":false},{"year":2009,"finding":"Systematic mutagenesis of Kv1.1 N255 confirms that asparagine at position 255 is required for normal voltage dependence and kinetics of gating; charged substitutions (N255D, N255E, N255Q) abolish function, while small hydrophobic or polar substitutions permit conduction with shifted activation voltage and faster activation kinetics.","method":"Expression of N255 mutants in HEK293 cells, cell surface biotinylation, whole-cell patch clamp","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic site-directed mutagenesis with functional electrophysiology and surface expression assay","pmids":["19903818"],"is_preprint":false},{"year":2010,"finding":"Kcna1-null mice display interictal cardiac abnormalities (AV conduction blocks, bradycardia, premature ventricular contractions) caused by excessive parasympathetic tone rather than intrinsic cardiac defect. Kv1.1 is expressed in juxtaparanodes of the vagus nerve; autonomic blockade (atropine) eliminates the AV conduction blocks, demonstrating brain-driven cardiac dysfunction.","method":"Simultaneous video EEG-ECG recordings in Kcna1-null mice, autonomic pharmacological blockade (atropine, propranolol), immunohistochemistry of vagus nerve","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection of autonomic pathway combined with knockout electrophysiology and immunolocalization","pmids":["20392939"],"is_preprint":false},{"year":2011,"finding":"NRG1 via its receptor ErbB4 increases the intrinsic excitability of fast-spiking parvalbumin-positive interneurons by decreasing voltage threshold for action potentials through Kv1.1 channels; this was established by pharmacological and genetic manipulation of ErbB4 in parvalbumin interneurons.","method":"Whole-cell patch clamp of FS-PV interneurons, ErbB4 conditional knockout in PV interneurons, NRG1 application, Kv1.1 pharmacology","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional genetic knockout and pharmacology with defined cellular electrophysiological readout","pmids":["22158511"],"is_preprint":false},{"year":2013,"finding":"mTOR activity regulates Kv1.1 mRNA translation via miR-129: when mTOR is active, miR-129 represses Kv1.1 translation; when mTOR is inactive, the RNA-binding protein HuD is freed from high-affinity target mRNA degradation, binds Kv1.1 mRNA, and promotes its translation. This establishes a bidirectional mTOR-HuD-miR-129 axis controlling dendritic Kv1.1 expression.","method":"miRNA identification, miR-129 reporter assays, HuD RNA immunoprecipitation, mTOR inhibition (rapamycin), competitive binding assays for HuD","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (miRNA reporter, RIP, competitive binding) in single study","pmids":["23836929"],"is_preprint":false},{"year":2013,"finding":"Kv1.1-Kv1.2 heteromers mediate a mechanosensitive K+ current (IKmech) in dorsal root ganglion mechanoreceptors; mechanosensitivity is attributed specifically to the Kv1.1 subunit through facilitation of voltage-dependent open probability. IKmech acts as a 'brake' opposing depolarization from MS cation currents in C-HTMRs, setting mechanical threshold. Dominant-negative Kv1.1 expression or Kv1.1 inhibition causes severe mechanical allodynia.","method":"Toxin profiling of IKmech, transgenic mouse studies (Kv1.1 dominant negative), whole-cell patch clamp of DRG mechanoreceptors, behavioral mechanical sensitivity testing","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — pharmacology, transgenic dominant negative, and electrophysiology with behavioral validation","pmids":["23473320"],"is_preprint":false},{"year":2013,"finding":"Loss of Kv1.1 in Kcna1-null mice enhances synaptic neurotransmitter release at mossy fiber and perforant path terminals in the CA3 region, reducing spike timing precision and producing pathologic high-frequency oscillations (fast ripples). This was recapitulated in wild-type slices with DTX-κ, confirming Kv1.1's role in presynaptic release control.","method":"Multielectrode array extracellular recordings in hippocampal slices, Kcna1-null mice, micro-dissection, paired-pulse ratio, DTX-κ pharmacology","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic knockout and pharmacological recapitulation with circuit-level analysis","pmids":["23466697"],"is_preprint":false},{"year":2013,"finding":"Oncogenic stress induces KCNA1 upregulation and redistribution from cytoplasm to the plasma membrane in a PKA-dependent manner: PKA phosphorylation at S446 retains Kv1.1 in the cytoplasm, and loss of PKA-induced phosphorylation (or PKA inhibition) allows membrane relocation. Membrane-localized Kv1.1 changes membrane potential and triggers cellular senescence, restricting oncogenesis.","method":"Loss-of-function genetic screen, phosphomimetic mutagenesis (S446), PKA activity manipulation, membrane potential measurements, transformation assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis and pharmacological PKA manipulation with senescence phenotype readout, single lab","pmids":["23774215"],"is_preprint":false},{"year":2014,"finding":"During temporal lobe epileptogenesis, two sequential phases of Kv1.1 repression occur: (1) an initial mTOR-dependent phase where mTOR activity reduces Kv1.1 expression, lowering AP firing threshold in CA1 pyramidal neurons; (2) a later mTOR-independent phase maintained by increased miR-129-5p, which persistently represses Kv1.1 mRNA translation.","method":"Kainic acid epilepsy model in rats, rapamycin treatment, miR-129-5p quantification, in vivo whole-cell patch clamp of CA1 neurons","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mTOR inhibitor, miRNA quantification, and in vivo electrophysiology in single lab","pmids":["25270294"],"is_preprint":false},{"year":2018,"finding":"LGI1 antibodies (patient-derived IgG) disrupt LGI1 interaction with ADAM23 (which interacts with presynaptic Kv1.1) and cause decreased total and synaptic levels of Kv1.1 in hippocampal neurons, leading to neuronal hyperexcitability, increased presynaptic glutamate release probability, and impaired long-term potentiation.","method":"Patient IgG cerebroventricular infusion in mice, confocal analysis of hippocampal slices, whole-cell patch clamp of dentate gyrus and CA1 neurons, field potential LTP recordings","journal":"Brain","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo IgG transfer model with patch clamp, imaging, and LTP recording in one study","pmids":["30346486"],"is_preprint":false},{"year":2018,"finding":"Two novel KCNA1 mutations (L319R and N255K) causing paroxysmal kinesigenic dyskinesia produce reduced K+ currents with altered gating and dominant negative effects on wild-type Kv1.1 in HEK293 cells; L319R also accelerates protein degradation via the proteasome pathway and disrupts membrane expression.","method":"Whole-exome sequencing, patch clamp in HEK293 cells, Western blot, proteasome inhibitor studies, surface expression assay","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — functional electrophysiology and biochemistry in HEK cells, single lab","pmids":["29294000"],"is_preprint":false},{"year":2019,"finding":"A recessive homozygous KCNA1 variant (p.Val368Leu) in the pore domain abolishes channel function; heterozygous co-expression with wild-type produces no dominant negative effect, distinguishing this from all previously described autosomal dominant KCNA1 mutations. This establishes KCNA1 loss of function via a recessive mechanism causing neonatal epileptic encephalopathy.","method":"Whole-exome sequencing, patch clamp of mutant-expressing cells, co-expression with wild-type","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — functional patch clamp with co-expression, single study/family","pmids":["31586945"],"is_preprint":false},{"year":2020,"finding":"Neuron-specific conditional Kcna1 knockout (using Synapsin1-Cre) is sufficient to cause epilepsy, premature death, and cardiorespiratory dysregulation, demonstrating that the brain-driven (neuronal) loss of Kv1.1 alone — without cardiac Kv1.1 deficiency — underlies SUDEP-associated phenotypes.","method":"Conditional knockout mice (floxed Kcna1 × Synapsin1-Cre), EEG, ECG, plethysmography, molecular confirmation of tissue-specific deletion","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional genetic approach with multi-system physiological recordings and molecular validation","pmids":["31978607"],"is_preprint":false},{"year":2003,"finding":"KCNE4 beta-subunit specifically inhibits Kv1.1 and Kv1.3 but not Kv1.2, Kv1.4, Kv1.5, or Kv4.3 homomeric channels; it also reduces current through Kv1.1/Kv1.2 heteromers. Confocal microscopy and Western blotting show Kv1.1 and KCNE4 co-localize at the cell surface.","method":"Xenopus oocyte and HEK293 cell co-expression, whole-cell patch clamp, confocal microscopy, Western blot","journal":"Biophysical journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — functional reconstitution in two expression systems with colocalization imaging","pmids":["12944270"],"is_preprint":false},{"year":1995,"finding":"Kv1.1 channel activity is required for thymocyte development: dendrotoxin blockade of Kv1.1 (and charybdotoxin blockade of Kv1.3) reduces thymocyte yield and alters developmental progression of CD4-CD8- thymocytes in fetal thymic organ culture.","method":"Patch clamp of murine thymocytes, RT-PCR, fetal thymic organ culture with DTX and CTX peptide blockers","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological channel block in organ culture with developmental readout, single lab","pmids":["7673227"],"is_preprint":false},{"year":1998,"finding":"Cyclic AMP elevation in C6 glioma cells accelerates Kv1.1 mRNA degradation, leading to reduced Kv1.1 protein and decreased sustained K+ current. Kv1.1 contributes to setting the resting membrane potential (DTX-I blocks 96% of sustained K+ current, shifting Vm from -40 to -7 mV).","method":"cAMP elevation (forskolin/IBMX) in C6 glioma, Northern blot, Western blot, whole-cell patch clamp, DTX-I pharmacology","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mRNA stability, protein, and functional current measurements in single lab","pmids":["9636212"],"is_preprint":false},{"year":2003,"finding":"Analysis of phosphorylation-dependent modulation shows PKA activation causes phosphorylation of intracellular Kv1.1 protein, followed by rapid translocation to the plasma membrane and increased current amplitude with altered voltage dependence. PKC activation does not directly phosphorylate Kv1.1 but induces Kv1.1 protein synthesis.","method":"Stable HEK293 transfection with Kv1.1, PKA/PKC activators, phospho-specific immunoprecipitation, subcellular fractionation, whole-cell patch clamp","journal":"Neuropharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical fractionation combined with electrophysiology, single lab","pmids":["12681381"],"is_preprint":false},{"year":2011,"finding":"RNA editing of Kv1.1 at position I400V generates 4-aminopyridine-insensitive Kv1.1 channels; fourfold increased I400V RNA editing in the entorhinal cortex of chronic epileptic rats accounts for the reduced ictogenic potential of 4-AP in this tissue.","method":"Sequencing of Kv1.1 mRNA from epileptic rat brain, two-electrode voltage clamp in Xenopus oocytes expressing edited vs unedited Kv1.1","journal":"Epilepsia","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — RNA editing quantification plus functional reconstitution of edited channel in oocytes","pmids":["21371023"],"is_preprint":false},{"year":2012,"finding":"The V408A knock-in mutation in Kv1.1 causes spontaneous myokymic discharges in motor nerve; two-photon Ca2+ imaging shows abnormal spontaneous Ca2+ signals in V408A motor nerve axons. Myokymic activity is exacerbated by fatigue, ischemia, and low temperature, identifying juxtaparanodal Kv1.1 as critical for dampening motor nerve axon excitability under stress.","method":"V408A knock-in mice, in vivo nerve-muscle preparations, two-photon Ca2+ imaging of motor nerve, compound muscle action potential recording, nerve axotomy","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knock-in genetic model with Ca2+ imaging and electrophysiology, multiple stressors tested","pmids":["22609489"],"is_preprint":false},{"year":2019,"finding":"Kv1.1 contributes to homeostatic depression of intrinsic excitability in CA1 pyramidal neurons in vivo: theta-burst-induced depression of excitability was attenuated by DTX-K (Kv1.1 blocker), indicating an axonal Kv1.1 mechanism distinct from dendritic Ih.","method":"Whole-cell patch clamp in anesthetized rats in vivo, theta-burst stimulation, dendrotoxin K pharmacology","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo patch clamp with selective pharmacology, single lab","pmids":["31774395"],"is_preprint":false},{"year":1999,"finding":"Kv1.1 is expressed in Kv1.1-positive cells in the absence of Kv1.1, ~50% of IKL remains and is still dendrotoxin-sensitive, suggesting Kv1.2 and/or Kv1.6 compensate in part by forming DTX-sensitive channels; full IKL requires Kv1.1 subunit participation.","method":"Patch clamp in MNTB neurons from Kcna1-null mice, dendrotoxin pharmacology","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with pharmacological dissection, single lab","pmids":["12611922"],"is_preprint":false}],"current_model":"KCNA1/Kv1.1 is a voltage-gated delayed-rectifier K+ channel that assembles cotranslationally into homo- or heterotetramers with other Kv1 subfamily subunits; it is palmitoylated at C243 (modulating voltage sensing), regulated by PKA (promoting membrane trafficking), PKC (inhibiting current via Rho GTPase-dependent mechanism), and arachidonic acid (accelerating gating kinetics); its dendritic expression is controlled by an mTOR–miR-129–HuD translational axis; it is critically localized to axonal juxtaparanodes and presynaptic terminals where it dampens neuronal excitability and controls neurotransmitter release, temporal precision of action potential firing, and mechanosensory thresholds; in the kidney DCT it sets membrane potential to facilitate TRPM6-mediated Mg2+ reabsorption; and loss-of-function or dominant-negative mutations cause episodic ataxia type 1, epilepsy, hyperalgesia, hypomagnesemia, and brain-driven cardiac arrhythmias underlying SUDEP."},"narrative":{"mechanistic_narrative":"KCNA1 encodes Kv1.1, a voltage-gated delayed-rectifier K+ channel that assembles cotranslationally into Shaker-family homo- and heterotetramers (with Kv1.2, Kv1.4, Kv1.5) and conducts a dendrotoxin-sensitive low-threshold K+ current that dampens neuronal excitability [PMID:7517498, PMID:8126562, PMID:12611922]. The protein localizes to axonal juxtaparanodes, presynaptic terminals, somata, and proximal dendrites, where it sets the membrane potential, controls presynaptic neurotransmitter release, and enforces temporal precision of action potential firing [PMID:8046438, PMID:14534254, PMID:23466697]. Through these roles Kv1.1 sets mechanosensory thresholds in DRG mechanoreceptors via Kv1.1/Kv1.2 heteromers [PMID:23473320], constrains motor-nerve axon excitability under metabolic stress [PMID:22609489], and acts as a homeostatic brake on intrinsic excitability in hippocampal pyramidal neurons [PMID:31774395]. Channel gating and surface availability are tuned by multiple inputs: palmitoylation at C243 and sialylation shift voltage dependence [PMID:15837928, PMID:8702582]; arachidonic acid released by iPLA2 accelerates gating [PMID:7852365]; PKA phosphorylation governs cytoplasm-to-membrane trafficking [PMID:12681381, PMID:23774215]; PKC inhibits current through a Rho GTPase pathway [PMID:10409113]; Gβγ and the aldoketoreductase β-subunit Kvβ1 modulate N-type inactivation [PMID:10064591, PMID:18222921]; and an mTOR–miR-129–HuD axis controls dendritic Kv1.1 mRNA translation [PMID:17023663, PMID:23836929]. In the kidney distal convoluted tubule Kv1.1 colocalizes with TRPM6 and sets a favorable membrane potential for Mg2+ reabsorption [PMID:19307729]. Dominant-negative and loss-of-function KCNA1 mutations cause episodic ataxia type 1, hypomagnesemia, paroxysmal kinesigenic dyskinesia, and epileptic encephalopathy, acting either by ER retention/aggregation of heterotetramers or by altered channel kinetics [PMID:9526001, PMID:11773313, PMID:19307729, PMID:29294000, PMID:31586945]; neuron-restricted Kv1.1 loss alone is sufficient to drive epilepsy and brain-driven cardiorespiratory dysregulation underlying SUDEP [PMID:20392939, PMID:31978607].","teleology":[{"year":1994,"claim":"Established that Kv1.1 is itself a pore-forming subunit producing a functional delayed-rectifier K+ current and that it assembles selectively with Shaker-family subunits, defining the molecular building block.","evidence":"Stable mammalian expression with whole-cell patch clamp and pharmacology; in vitro translation, immunopurification, and pulse-chase of cotranslational assembly","pmids":["7517498","8126562"],"confidence":"High","gaps":["Subunit stoichiometry in native tissue not resolved","Glycosylation role left open for surface trafficking"]},{"year":1994,"claim":"Defined the subcellular distribution of Kv1.1 to juxtaparanodes, synaptic terminals, somata, and dendrites, anchoring later excitability functions to specific neuronal compartments.","evidence":"Immunocytochemistry of mouse brain sections, contrasted with Kv1.2","pmids":["8046438"],"confidence":"High","gaps":["Did not establish functional consequence of compartmental targeting","Targeting/anchoring mechanism unknown"]},{"year":1996,"claim":"Identified lipid- and glycan-based modulation of voltage sensing, showing arachidonic acid and sialic acid residues tune Kv1.1 gating without altering surface expression.","evidence":"Patch clamp in Sf9 with iPLA2 and fatty acid application; expression in glycosylation-deficient CHO Lec cells with sialidase treatment","pmids":["7852365","8702582"],"confidence":"High","gaps":["Physiological source of arachidonic acid in vivo not defined","Whether sialylation state is regulated in neurons unknown"]},{"year":1998,"claim":"Demonstrated through knockdown and knockout that Kv1.1 is required for hippocampal memory and for nociceptive/antinociceptive signaling, moving from biophysics to organismal function.","evidence":"Antisense knockdown with patch clamp and behavior; Kcna1 knockout mice with nociception assays","pmids":["9114006","9718989"],"confidence":"Medium","gaps":["Single-lab behavioral findings","Circuit-level basis of memory deficit not dissected"]},{"year":1999,"claim":"Resolved the dominant-negative disease mechanism, showing truncated/EA1 subunits coassemble with wild-type and either trap heterotetramers in the ER or alter gating in defined stoichiometries.","evidence":"GH3/oocyte co-expression, double IP, subcellular fractionation, confocal imaging, TEA-tagging, tandem-linked subunits, single-channel analysis","pmids":["9334228","9526001","10428758"],"confidence":"High","gaps":["ER quality-control machinery retaining mutant channels not identified","Genotype–phenotype severity correlation incomplete"]},{"year":1999,"claim":"Identified protein partners and signaling inputs (Gβγ, PKC/Rho, Kvβ1, KCNE4) that regulate Kv1.1 current and inactivation, expanding the channel into a regulated signaling node.","evidence":"GST pulldown and Co-IP for Gβγ; phorbol ester/C3 toxin and mutagenesis for PKC; oocyte/HEK co-expression and confocal colocalization for KCNE4; enzymatic reconstitution for Kvβ1","pmids":["10064591","10409113","18222921","12944270"],"confidence":"High","gaps":["Physiological contexts engaging each modulator not established","Direct structural interfaces largely undefined"]},{"year":2003,"claim":"Quantified Kv1.1's contribution to the low-threshold K+ current in auditory neurons and established its in vivo role in temporal precision, with partial subunit compensation by Kv1.2/Kv1.6.","evidence":"Patch clamp in Kcna1-null brainstem slices, DTX-K pharmacology, and in vivo single-unit recordings in VCN/MNTB","pmids":["12611922","14534254","16672305","11290530"],"confidence":"High","gaps":["Mechanism of heteromeric compensation not fully resolved","Contribution of accessory subunits in vivo unquantified"]},{"year":2005,"claim":"Mapped post-translational palmitoylation at C243 as a voltage-sensing modulator, linking membrane attachment of the S2-S3 linker to gating.","evidence":"[3H]palmitate labeling, mutagenesis, and patch clamp in Sf9 cells","pmids":["15837928"],"confidence":"High","gaps":["Palmitoyl-transferase responsible not identified","Dynamic regulation of palmitoylation in neurons unknown"]},{"year":2006,"claim":"Established translational control of dendritic Kv1.1 by mTOR, later refined into a bidirectional mTOR–miR-129–HuD axis, explaining activity-dependent and disease-associated changes in channel abundance.","evidence":"Rapamycin/NMDA blockade with Kaede local-synthesis reporter; miR-129 reporters, HuD RIP, and competitive binding assays","pmids":["17023663","23836929"],"confidence":"High","gaps":["Upstream signals setting mTOR tone in dendrites not defined","Selectivity of miR-129/HuD for Kv1.1 vs other targets unclear"]},{"year":2009,"claim":"Extended Kv1.1 function beyond neurons to the kidney DCT, where it colocalizes with TRPM6 and a dominant-negative mutation causes hypomagnesemia by abolishing the favorable membrane potential for Mg2+ reabsorption.","evidence":"Positional cloning, HEK patch clamp with wild-type co-expression, kidney immunohistochemistry; systematic N255 mutagenesis with surface biotinylation","pmids":["19307729","19903818"],"confidence":"High","gaps":["Whether DCT Kv1.1 is regulated by hormonal Mg2+ signals unknown","Channel partners in renal epithelium beyond TRPM6 not defined"]},{"year":2013,"claim":"Defined Kv1.1's presynaptic and mechanosensory roles, showing it brakes neurotransmitter release and sets DRG mechanical thresholds, and connected it to the LGI1–ADAM23 presynaptic complex.","evidence":"MEA recordings and DTX-κ in Kcna1-null hippocampus; toxin profiling and dominant-negative transgenics in DRG with behavior; patient-IgG transfer with patch clamp and LTP","pmids":["23466697","23473320","30346486"],"confidence":"High","gaps":["Molecular basis of Kv1.1 mechanosensitivity not structurally defined","How LGI1–ADAM23 stabilizes presynaptic Kv1.1 mechanistically unresolved"]},{"year":2020,"claim":"Demonstrated that neuron-restricted loss of Kv1.1 is sufficient to produce epilepsy and brain-driven cardiorespiratory dysregulation, localizing SUDEP-relevant phenotypes to the central nervous system.","evidence":"Synapsin1-Cre conditional Kcna1 knockout with EEG, ECG, plethysmography; earlier autonomic pharmacological dissection in global knockouts","pmids":["31978607","20392939"],"confidence":"High","gaps":["Specific neuronal circuits driving lethal events not pinpointed","Therapeutic reversibility not addressed"]},{"year":null,"claim":"How the diverse regulatory inputs (palmitoylation, PKA/PKC, Gβγ, mTOR-miR-129-HuD, RNA editing) are integrated in vivo to set Kv1.1 availability in specific compartments remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of compartment-specific regulation","Interplay between transcriptional, translational, and post-translational control untested in native neurons"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,15,24,39]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[23]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,24,31,37]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[6,13]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[31,40]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[17,29,30,43]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[24,0]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,24,34,35,36]}],"complexes":["Kv1 (Shaker) channel tetramer","Kv1.1/Kvβ1 channel complex","Kv1.1/Kv1.2 heteromeric channel"],"partners":["KCNA2","KCNA4","KCNAB1","KCNE4","TRPM6","ADAM23","LGI1"],"other_free_text":[]}},"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":"7517498","id":"PMC_7517498","title":"Pharmacological 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Biophysical characterization showed it resembles the K+ channel in C6 glioma cells and astrocytes.\",\n      \"method\": \"Stable expression in mammalian cell lines, whole-cell patch clamp, pharmacological profiling\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct electrophysiological reconstitution in mammalian cells with pharmacological characterization, widely replicated\",\n      \"pmids\": [\"7517498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Kv1.1 protein is localized to synaptic terminals, somata, juxta-paranodal regions of myelinated axons, unmyelinated axons, specialized junctions among axons, and proximal dendrites in the mouse brain, with region-specific distribution distinct from Kv1.2.\",\n      \"method\": \"Immunocytochemistry in mouse brain sections\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct immunolocalization replicated across multiple brain regions and labs\",\n      \"pmids\": [\"8046438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Kv1.1 assembles cotranslationally with other Shaker-like subunits (Kv1.4) but not with non-Shaker Kv2.1; N207 glycosylation occurs but is not required for subunit assembly, surface transport, or function; surface channels exist as two species (~57 and ~59 kDa) with precursor-product relationship.\",\n      \"method\": \"Immune purification of in vitro translations and transfected mouse L-cells, pulse-chase metabolic labeling, site-directed mutagenesis of glycosylation site, SDS-PAGE\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution, mutagenesis, and pulse-chase labeling in single rigorous study\",\n      \"pmids\": [\"8126562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Ca2+-independent phospholipase A2 (iPLA2) modulates Kv1.1 channel kinetics by releasing arachidonic acid, which accelerates both activation and induces inactivation of the channel. The effect is arachidonic-acid specific and independent of eicosanoid metabolites.\",\n      \"method\": \"Whole-cell patch clamp of Sf9 cells expressing human Kv1.1, intracellular administration of iPLA2, mechanism-based inhibitor, exogenous fatty acid application\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution in Sf9 cells with multiple controls, mechanism-based inhibitor, and fatty acid specificity tests\",\n      \"pmids\": [\"7852365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Sialic acid residues on Kv1.1 modulate its voltage dependence of activation (shifting V1/2 to more positive voltages when sialidation is prevented) and slow activation kinetics; sialic acids act as negative surface charges that influence the local electric field at the voltage sensor. Glycosylation is not required for cell surface expression.\",\n      \"method\": \"Expression of Kv1.1 in glycosylation-deficient CHO Lec mutant cell lines, whole-cell patch clamp, sialidase treatment, Ca2+ application\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — functional reconstitution with glycosylation-deficient cell lines and enzyme treatment, multiple orthogonal methods\",\n      \"pmids\": [\"8702582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Antisense oligonucleotide-mediated knockdown of Kv1.1 in hippocampal neurons reduces late-rectifying K+ current in dentate granule cells and impairs associative memory (passive avoidance and spatial memory tasks) in mice and rats, demonstrating Kv1.1 is required for hippocampus-dependent memory formation.\",\n      \"method\": \"Intracerebroventricular antisense oligonucleotide injection, whole-cell patch clamp of dentate granule cells, behavioral testing (passive avoidance, Morris water maze)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antisense knockdown with electrophysiological and behavioral readouts in two species, single lab\",\n      \"pmids\": [\"9114006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Truncated Kv1.1 (Kv1.1N206Tag) forms heteromultimeric complexes with native Kv1.4 and Kv1.5 channels and traps these complexes in the endoplasmic reticulum, preventing surface expression — establishing a dominant-negative mechanism via ER retention.\",\n      \"method\": \"Transient expression in GH3 cells, double immunoprecipitation, subcellular fractionation, immunofluorescence/confocal microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — Co-IP, subcellular fractionation, and confocal colocalization in single study\",\n      \"pmids\": [\"9334228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Episodic ataxia type 1 (EA1) mutations in Kv1.1 affect channel function by two mechanisms: dominant negative effects (most mutations), or haploinsufficiency (R239S and F249I, which show reduced protein levels). EA subunits coassemble with wild-type subunits in mixed stoichiometries. Channels bearing EA mutations show lower current amplitudes and altered gating.\",\n      \"method\": \"Expression of EA mutant cRNAs in Xenopus oocytes, co-injection experiments, TEA-tagging to discriminate subunit contribution, Western blot\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — functional reconstitution with mutagenesis, pharmacological subunit discrimination, and protein quantification\",\n      \"pmids\": [\"9526001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Kv1.1 loss-of-function (Kcna1 knockout) causes thermal hyperalgesia and increased formalin-induced nociception, and blunts morphine-induced antinociception, establishing Kv1.1 as a regulator of nociceptive and antinociceptive signaling.\",\n      \"method\": \"Kcna1 knockout mice, paw flick assay, hot plate assay, formalin test, morphine antinociception assay\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with multiple behavioral nociceptive readouts, single lab\",\n      \"pmids\": [\"9718989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"EA1 mutations V408A and E325D in Kv1.1, when co-assembled with Kv1.2 using tandem-linked subunits, produce heteromeric channels with altered kinetics of activation, deactivation, C-type inactivation, and voltage dependence. V408A reduces mean open duration ~3-fold in single-channel analysis, destabilizing the open state of both homomeric and heteromeric channels.\",\n      \"method\": \"Tandemly linked subunit expression in Xenopus oocytes, single-channel patch clamp, macroscopic current analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — single-channel reconstitution with tandem subunits and multiple gating parameter analyses\",\n      \"pmids\": [\"10428758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Protein kinase C (PKC) activation inhibits Kv1.1 current by up to 90% via a mechanism requiring a C3 exoenzyme substrate (Rho GTPase pathway), without altering activation gating or reducing membrane channel protein. Direct phosphorylation of Kv1.1 by PKC was not responsible.\",\n      \"method\": \"Xenopus oocyte expression, phorbol ester treatment, PKC inhibitors, site-directed mutagenesis of PKC phosphorylation sites, Western blot, botulinum toxin C3 injection\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis of phosphorylation sites combined with toxin-based pathway dissection, single lab\",\n      \"pmids\": [\"10409113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Dendrotoxin K (DTXk) selectively inhibits Kv1.1-containing channels; its K3 residue in the 310-helical N-terminal region is critical for Kv1.1 recognition (K3A mutation causes ~1246-fold loss of potency), while W25 and K26 in the beta-turn are also important for toxin-channel interaction.\",\n      \"method\": \"Site-directed mutagenesis of DTXk, radioligand binding competition assay with [125I]DTXk and [125I]alphaDTX to rat brain membranes, two-electrode voltage clamp in Xenopus oocytes expressing Kv1.1\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with binding and functional assays, identifies specific interaction residues\",\n      \"pmids\": [\"10429207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"G protein beta-gamma (Gbeta1gamma2) subunits directly interact with Kv1.1 and Kvbeta1.1, promote co-assembly of more Kvbeta1.1 with Kv1.1, and increase the extent of N-type (A-type) inactivation of Kv1.1/Kvbeta1.1 channels. This effect is occluded by microfilament disruption and requires co-expression during channel assembly rather than acute application.\",\n      \"method\": \"Xenopus oocyte co-expression, GST pulldown of Gbeta1gamma2 with Kv1.1/Kvbeta1.1 fusion fragments, co-immunoprecipitation, electrophysiology, C-terminal betaARK fragment scavenging\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — GST pulldown, Co-IP, and functional electrophysiology in single study\",\n      \"pmids\": [\"10064591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The R417stop truncation mutation in Kv1.1 (EA1) impairs both tetramerization with wild-type subunits and membrane targeting of heterotetramers, trapping channels intracellularly. Other EA1 mutations (V404I, P244H) do not affect tetramerization or trafficking but alter channel kinetics.\",\n      \"method\": \"Xenopus oocyte expression, electrophysiology, pharmacological subunit discrimination, confocal laser scanning microscopy of EGFP-tagged subunits\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — functional electrophysiology, pharmacological discrimination, and GFP-based trafficking imaging in one study\",\n      \"pmids\": [\"11773313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"EA1 nonsense mutations in Kv1.1 cause intracellular aggregation and detergent insolubility of the mutant protein, which can be transferred to co-assembled Kv1 alpha- and Kvbeta-subunits. EA1 missense mutations, in contrast, do not alter folding or trafficking compared to wild-type.\",\n      \"method\": \"Heterologous expression, detergent solubility assay, immunostaining, co-assembly analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods in single lab study\",\n      \"pmids\": [\"11679591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Kv1.1 subunits contribute ~50% of the low voltage-activated potassium current (IKL) in auditory MNTB neurons. Kcna1 knockout mice show approximately halved IKL amplitude, doubled action potential firing, and halved rheobase. Residual IKL in knockout neurons is carried by Kv1.2/Kv1.6-containing channels (DTX-sensitive).\",\n      \"method\": \"Whole-cell patch clamp in brainstem slices from Kcna1-null mice and wild-type littermates, dendrotoxin pharmacology\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout combined with pharmacology and electrophysiology, replicated across genotypes\",\n      \"pmids\": [\"12611922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Kv1.1 glycosylation (N-linked, at S1-S2 linker) does not affect protein stability, cellular localization, or trafficking to the cell surface, in contrast to Kv1.4. A pore region determinant in Kv1.1 vs Kv1.4 dictates whether glycosylation influences trafficking.\",\n      \"method\": \"Prevention of N-glycosylation (tunicamycin, mutagenesis), Western blot for protein stability, immunocytochemistry for cellular localization, chimeric channel construction\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis and chimeric channels with protein stability and trafficking assays\",\n      \"pmids\": [\"14688283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Kv1.1 is expressed in the medial nucleus of the trapezoid body (MNTB) and is required for temporal precision (low jitter) in auditory signal processing in vivo; Kcna1-null mice show increased first-spike latency jitter in VCN and MNTB neurons and failure to follow high-frequency amplitude-modulated stimuli.\",\n      \"method\": \"In vivo single-unit recordings from VCN and MNTB neurons of Kcna1-null and wild-type mice during auditory stimulation\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo electrophysiology in genetic knockout, replicated across multiple auditory nuclei\",\n      \"pmids\": [\"14534254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Truncation of Kv1.1 at amino acid 230 (mceph mutation, 11-bp deletion) in mice causes megencephaly; the truncated protein lacks C-terminal domains, and sequestration of Kv1.2 and Kv1.3 proteins is observed (reduced protein levels despite normal mRNA), suggesting dominant interaction at the protein level. Seizures occur in these mice.\",\n      \"method\": \"Positional cloning, sequencing, immunoblot for Kv1.2/Kv1.3 protein levels, in situ hybridization for mRNA, EEG\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic model with protein-level analysis, single lab\",\n      \"pmids\": [\"14686897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human Kv1.1 is palmitoylated at cysteine C243 in the cytosolic S2-S3 linker domain; preventing palmitoylation at C243 by mutagenesis causes a 20-mV leftward shift in the current-voltage relationship, implicating palmitoylation at C243 in modulating voltage sensing through protein-membrane interactions.\",\n      \"method\": \"Heterologous expression in Sf9 cells, [3H]palmitate radiolabeling, chemical stability studies, site-directed mutagenesis, whole-cell patch clamp\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — covalent radiolabeling, mutagenesis, and functional electrophysiology in single rigorous study\",\n      \"pmids\": [\"15837928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Kv1.1-containing channels (identified by dendrotoxin-K) underlie low-threshold K+ current (Ikl) in MNTB neurons and are critical for temporal precision of spike initiation; partial (~50%) reduction of Ikl by 3 nM DTX-K or Kcna1 knockout similarly increases AP jitter and latency, especially at high stimulation rates.\",\n      \"method\": \"Whole-cell patch clamp in mouse brain slices, selective DTX-K pharmacology at multiple concentrations, comparison with Kcna1-/- mice\",\n      \"journal\": \"Journal of neurophysiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — pharmacology and genetics converge on same phenotype, multiple concentrations tested\",\n      \"pmids\": [\"16672305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"mTOR activity suppresses Kv1.1 mRNA translation in dendrites; inhibition of mTOR with rapamycin or of NMDA receptors increases Kv1.1 protein in hippocampal neuron dendrites (but not axons). Local dendritic synthesis of Kv1.1 was demonstrated using a Kaede photoconvertible reporter.\",\n      \"method\": \"Rapamycin treatment of hippocampal neurons, Kv1.1-Kaede reporter for local protein synthesis, immunostaining, NMDA receptor blockade\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell reporter for local synthesis, pharmacological manipulation, compartment-specific protein quantification\",\n      \"pmids\": [\"17023663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"EA1 mutations E325D, V404I, V408A, and I177N in Kv1.1 alter N-type inactivation properties of heteromeric Kv1.4-1.1 channels co-assembled with Kvbeta1.1 or Kvbeta1.2: they decrease the rate and degree of N-type inactivation, accelerate recovery from fast inactivation, and shift steady-state inactivation voltage dependence.\",\n      \"method\": \"Expression of tandemly linked Kv1.4-1.1 constructs with EA1 mutations in Xenopus oocytes, two-electrode voltage clamp\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — tandem-linked subunit reconstitution with systematic mutagenesis and multiple gating analyses\",\n      \"pmids\": [\"17156368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Kvbeta1 is a functional aldoketoreductase; oxidation of the NADPH cofactor bound to Kvbeta1 (either enzymatically by a substrate or non-enzymatically by H2O2 or NADP+) causes a large increase in open Kv1.1 channel current. This cofactor oxidation rate is ~2-fold faster at 0 mV than at -100 mV, indicating that Kv1.1 voltage-dependent conformational changes regulate Kvbeta1 enzymatic activity.\",\n      \"method\": \"Patch clamp of Kv1.1 + Kvbeta1 expressed in oocytes, substrate addition, H2O2/NADP+ treatment, deletion mutagenesis of Kv1.1 C-terminus\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic and functional reconstitution with multiple reagents and mutagenesis\",\n      \"pmids\": [\"18222921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A missense mutation N255D in KCNA1 (S3 transmembrane segment) causes autosomal dominant hypomagnesemia by creating a non-functional channel with dominant negative effect on wild-type Kv1.1. Kv1.1 is expressed in the kidney distal convoluted tubule (DCT) where it colocalizes with the Mg2+ transporter TRPM6 on the luminal membrane, establishing a favorable membrane potential for TRPM6-mediated Mg2+ reabsorption.\",\n      \"method\": \"Positional cloning, patch clamp of N255D-expressing HEK cells, co-expression with wild-type, immunohistochemistry of kidney sections for Kv1.1/TRPM6 colocalization\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — patch clamp, dominant-negative testing, and immunohistochemical colocalization in kidney, single rigorous study\",\n      \"pmids\": [\"19307729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Systematic mutagenesis of Kv1.1 N255 confirms that asparagine at position 255 is required for normal voltage dependence and kinetics of gating; charged substitutions (N255D, N255E, N255Q) abolish function, while small hydrophobic or polar substitutions permit conduction with shifted activation voltage and faster activation kinetics.\",\n      \"method\": \"Expression of N255 mutants in HEK293 cells, cell surface biotinylation, whole-cell patch clamp\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic site-directed mutagenesis with functional electrophysiology and surface expression assay\",\n      \"pmids\": [\"19903818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Kcna1-null mice display interictal cardiac abnormalities (AV conduction blocks, bradycardia, premature ventricular contractions) caused by excessive parasympathetic tone rather than intrinsic cardiac defect. Kv1.1 is expressed in juxtaparanodes of the vagus nerve; autonomic blockade (atropine) eliminates the AV conduction blocks, demonstrating brain-driven cardiac dysfunction.\",\n      \"method\": \"Simultaneous video EEG-ECG recordings in Kcna1-null mice, autonomic pharmacological blockade (atropine, propranolol), immunohistochemistry of vagus nerve\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection of autonomic pathway combined with knockout electrophysiology and immunolocalization\",\n      \"pmids\": [\"20392939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NRG1 via its receptor ErbB4 increases the intrinsic excitability of fast-spiking parvalbumin-positive interneurons by decreasing voltage threshold for action potentials through Kv1.1 channels; this was established by pharmacological and genetic manipulation of ErbB4 in parvalbumin interneurons.\",\n      \"method\": \"Whole-cell patch clamp of FS-PV interneurons, ErbB4 conditional knockout in PV interneurons, NRG1 application, Kv1.1 pharmacology\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional genetic knockout and pharmacology with defined cellular electrophysiological readout\",\n      \"pmids\": [\"22158511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"mTOR activity regulates Kv1.1 mRNA translation via miR-129: when mTOR is active, miR-129 represses Kv1.1 translation; when mTOR is inactive, the RNA-binding protein HuD is freed from high-affinity target mRNA degradation, binds Kv1.1 mRNA, and promotes its translation. This establishes a bidirectional mTOR-HuD-miR-129 axis controlling dendritic Kv1.1 expression.\",\n      \"method\": \"miRNA identification, miR-129 reporter assays, HuD RNA immunoprecipitation, mTOR inhibition (rapamycin), competitive binding assays for HuD\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (miRNA reporter, RIP, competitive binding) in single study\",\n      \"pmids\": [\"23836929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Kv1.1-Kv1.2 heteromers mediate a mechanosensitive K+ current (IKmech) in dorsal root ganglion mechanoreceptors; mechanosensitivity is attributed specifically to the Kv1.1 subunit through facilitation of voltage-dependent open probability. IKmech acts as a 'brake' opposing depolarization from MS cation currents in C-HTMRs, setting mechanical threshold. Dominant-negative Kv1.1 expression or Kv1.1 inhibition causes severe mechanical allodynia.\",\n      \"method\": \"Toxin profiling of IKmech, transgenic mouse studies (Kv1.1 dominant negative), whole-cell patch clamp of DRG mechanoreceptors, behavioral mechanical sensitivity testing\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — pharmacology, transgenic dominant negative, and electrophysiology with behavioral validation\",\n      \"pmids\": [\"23473320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss of Kv1.1 in Kcna1-null mice enhances synaptic neurotransmitter release at mossy fiber and perforant path terminals in the CA3 region, reducing spike timing precision and producing pathologic high-frequency oscillations (fast ripples). This was recapitulated in wild-type slices with DTX-κ, confirming Kv1.1's role in presynaptic release control.\",\n      \"method\": \"Multielectrode array extracellular recordings in hippocampal slices, Kcna1-null mice, micro-dissection, paired-pulse ratio, DTX-κ pharmacology\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout and pharmacological recapitulation with circuit-level analysis\",\n      \"pmids\": [\"23466697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Oncogenic stress induces KCNA1 upregulation and redistribution from cytoplasm to the plasma membrane in a PKA-dependent manner: PKA phosphorylation at S446 retains Kv1.1 in the cytoplasm, and loss of PKA-induced phosphorylation (or PKA inhibition) allows membrane relocation. Membrane-localized Kv1.1 changes membrane potential and triggers cellular senescence, restricting oncogenesis.\",\n      \"method\": \"Loss-of-function genetic screen, phosphomimetic mutagenesis (S446), PKA activity manipulation, membrane potential measurements, transformation assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis and pharmacological PKA manipulation with senescence phenotype readout, single lab\",\n      \"pmids\": [\"23774215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"During temporal lobe epileptogenesis, two sequential phases of Kv1.1 repression occur: (1) an initial mTOR-dependent phase where mTOR activity reduces Kv1.1 expression, lowering AP firing threshold in CA1 pyramidal neurons; (2) a later mTOR-independent phase maintained by increased miR-129-5p, which persistently represses Kv1.1 mRNA translation.\",\n      \"method\": \"Kainic acid epilepsy model in rats, rapamycin treatment, miR-129-5p quantification, in vivo whole-cell patch clamp of CA1 neurons\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mTOR inhibitor, miRNA quantification, and in vivo electrophysiology in single lab\",\n      \"pmids\": [\"25270294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LGI1 antibodies (patient-derived IgG) disrupt LGI1 interaction with ADAM23 (which interacts with presynaptic Kv1.1) and cause decreased total and synaptic levels of Kv1.1 in hippocampal neurons, leading to neuronal hyperexcitability, increased presynaptic glutamate release probability, and impaired long-term potentiation.\",\n      \"method\": \"Patient IgG cerebroventricular infusion in mice, confocal analysis of hippocampal slices, whole-cell patch clamp of dentate gyrus and CA1 neurons, field potential LTP recordings\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo IgG transfer model with patch clamp, imaging, and LTP recording in one study\",\n      \"pmids\": [\"30346486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Two novel KCNA1 mutations (L319R and N255K) causing paroxysmal kinesigenic dyskinesia produce reduced K+ currents with altered gating and dominant negative effects on wild-type Kv1.1 in HEK293 cells; L319R also accelerates protein degradation via the proteasome pathway and disrupts membrane expression.\",\n      \"method\": \"Whole-exome sequencing, patch clamp in HEK293 cells, Western blot, proteasome inhibitor studies, surface expression assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — functional electrophysiology and biochemistry in HEK cells, single lab\",\n      \"pmids\": [\"29294000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A recessive homozygous KCNA1 variant (p.Val368Leu) in the pore domain abolishes channel function; heterozygous co-expression with wild-type produces no dominant negative effect, distinguishing this from all previously described autosomal dominant KCNA1 mutations. This establishes KCNA1 loss of function via a recessive mechanism causing neonatal epileptic encephalopathy.\",\n      \"method\": \"Whole-exome sequencing, patch clamp of mutant-expressing cells, co-expression with wild-type\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — functional patch clamp with co-expression, single study/family\",\n      \"pmids\": [\"31586945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Neuron-specific conditional Kcna1 knockout (using Synapsin1-Cre) is sufficient to cause epilepsy, premature death, and cardiorespiratory dysregulation, demonstrating that the brain-driven (neuronal) loss of Kv1.1 alone — without cardiac Kv1.1 deficiency — underlies SUDEP-associated phenotypes.\",\n      \"method\": \"Conditional knockout mice (floxed Kcna1 × Synapsin1-Cre), EEG, ECG, plethysmography, molecular confirmation of tissue-specific deletion\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional genetic approach with multi-system physiological recordings and molecular validation\",\n      \"pmids\": [\"31978607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"KCNE4 beta-subunit specifically inhibits Kv1.1 and Kv1.3 but not Kv1.2, Kv1.4, Kv1.5, or Kv4.3 homomeric channels; it also reduces current through Kv1.1/Kv1.2 heteromers. Confocal microscopy and Western blotting show Kv1.1 and KCNE4 co-localize at the cell surface.\",\n      \"method\": \"Xenopus oocyte and HEK293 cell co-expression, whole-cell patch clamp, confocal microscopy, Western blot\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — functional reconstitution in two expression systems with colocalization imaging\",\n      \"pmids\": [\"12944270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Kv1.1 channel activity is required for thymocyte development: dendrotoxin blockade of Kv1.1 (and charybdotoxin blockade of Kv1.3) reduces thymocyte yield and alters developmental progression of CD4-CD8- thymocytes in fetal thymic organ culture.\",\n      \"method\": \"Patch clamp of murine thymocytes, RT-PCR, fetal thymic organ culture with DTX and CTX peptide blockers\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological channel block in organ culture with developmental readout, single lab\",\n      \"pmids\": [\"7673227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Cyclic AMP elevation in C6 glioma cells accelerates Kv1.1 mRNA degradation, leading to reduced Kv1.1 protein and decreased sustained K+ current. Kv1.1 contributes to setting the resting membrane potential (DTX-I blocks 96% of sustained K+ current, shifting Vm from -40 to -7 mV).\",\n      \"method\": \"cAMP elevation (forskolin/IBMX) in C6 glioma, Northern blot, Western blot, whole-cell patch clamp, DTX-I pharmacology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mRNA stability, protein, and functional current measurements in single lab\",\n      \"pmids\": [\"9636212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Analysis of phosphorylation-dependent modulation shows PKA activation causes phosphorylation of intracellular Kv1.1 protein, followed by rapid translocation to the plasma membrane and increased current amplitude with altered voltage dependence. PKC activation does not directly phosphorylate Kv1.1 but induces Kv1.1 protein synthesis.\",\n      \"method\": \"Stable HEK293 transfection with Kv1.1, PKA/PKC activators, phospho-specific immunoprecipitation, subcellular fractionation, whole-cell patch clamp\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical fractionation combined with electrophysiology, single lab\",\n      \"pmids\": [\"12681381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RNA editing of Kv1.1 at position I400V generates 4-aminopyridine-insensitive Kv1.1 channels; fourfold increased I400V RNA editing in the entorhinal cortex of chronic epileptic rats accounts for the reduced ictogenic potential of 4-AP in this tissue.\",\n      \"method\": \"Sequencing of Kv1.1 mRNA from epileptic rat brain, two-electrode voltage clamp in Xenopus oocytes expressing edited vs unedited Kv1.1\",\n      \"journal\": \"Epilepsia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — RNA editing quantification plus functional reconstitution of edited channel in oocytes\",\n      \"pmids\": [\"21371023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The V408A knock-in mutation in Kv1.1 causes spontaneous myokymic discharges in motor nerve; two-photon Ca2+ imaging shows abnormal spontaneous Ca2+ signals in V408A motor nerve axons. Myokymic activity is exacerbated by fatigue, ischemia, and low temperature, identifying juxtaparanodal Kv1.1 as critical for dampening motor nerve axon excitability under stress.\",\n      \"method\": \"V408A knock-in mice, in vivo nerve-muscle preparations, two-photon Ca2+ imaging of motor nerve, compound muscle action potential recording, nerve axotomy\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in genetic model with Ca2+ imaging and electrophysiology, multiple stressors tested\",\n      \"pmids\": [\"22609489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Kv1.1 contributes to homeostatic depression of intrinsic excitability in CA1 pyramidal neurons in vivo: theta-burst-induced depression of excitability was attenuated by DTX-K (Kv1.1 blocker), indicating an axonal Kv1.1 mechanism distinct from dendritic Ih.\",\n      \"method\": \"Whole-cell patch clamp in anesthetized rats in vivo, theta-burst stimulation, dendrotoxin K pharmacology\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo patch clamp with selective pharmacology, single lab\",\n      \"pmids\": [\"31774395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Kv1.1 is expressed in Kv1.1-positive cells in the absence of Kv1.1, ~50% of IKL remains and is still dendrotoxin-sensitive, suggesting Kv1.2 and/or Kv1.6 compensate in part by forming DTX-sensitive channels; full IKL requires Kv1.1 subunit participation.\",\n      \"method\": \"Patch clamp in MNTB neurons from Kcna1-null mice, dendrotoxin pharmacology\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with pharmacological dissection, single lab\",\n      \"pmids\": [\"12611922\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KCNA1/Kv1.1 is a voltage-gated delayed-rectifier K+ channel that assembles cotranslationally into homo- or heterotetramers with other Kv1 subfamily subunits; it is palmitoylated at C243 (modulating voltage sensing), regulated by PKA (promoting membrane trafficking), PKC (inhibiting current via Rho GTPase-dependent mechanism), and arachidonic acid (accelerating gating kinetics); its dendritic expression is controlled by an mTOR–miR-129–HuD translational axis; it is critically localized to axonal juxtaparanodes and presynaptic terminals where it dampens neuronal excitability and controls neurotransmitter release, temporal precision of action potential firing, and mechanosensory thresholds; in the kidney DCT it sets membrane potential to facilitate TRPM6-mediated Mg2+ reabsorption; and loss-of-function or dominant-negative mutations cause episodic ataxia type 1, epilepsy, hyperalgesia, hypomagnesemia, and brain-driven cardiac arrhythmias underlying SUDEP.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KCNA1 encodes Kv1.1, a voltage-gated delayed-rectifier K+ channel that assembles cotranslationally into Shaker-family homo- and heterotetramers (with Kv1.2, Kv1.4, Kv1.5) and conducts a dendrotoxin-sensitive low-threshold K+ current that dampens neuronal excitability [#0, #2, #15]. The protein localizes to axonal juxtaparanodes, presynaptic terminals, somata, and proximal dendrites, where it sets the membrane potential, controls presynaptic neurotransmitter release, and enforces temporal precision of action potential firing [#1, #17, #30]. Through these roles Kv1.1 sets mechanosensory thresholds in DRG mechanoreceptors via Kv1.1/Kv1.2 heteromers [#29], constrains motor-nerve axon excitability under metabolic stress [#42], and acts as a homeostatic brake on intrinsic excitability in hippocampal pyramidal neurons [#43]. Channel gating and surface availability are tuned by multiple inputs: palmitoylation at C243 and sialylation shift voltage dependence [#19, #4]; arachidonic acid released by iPLA2 accelerates gating [#3]; PKA phosphorylation governs cytoplasm-to-membrane trafficking [#40, #31]; PKC inhibits current through a Rho GTPase pathway [#10]; Gβγ and the aldoketoreductase β-subunit Kvβ1 modulate N-type inactivation [#12, #23]; and an mTOR–miR-129–HuD axis controls dendritic Kv1.1 mRNA translation [#21, #28]. In the kidney distal convoluted tubule Kv1.1 colocalizes with TRPM6 and sets a favorable membrane potential for Mg2+ reabsorption [#24]. Dominant-negative and loss-of-function KCNA1 mutations cause episodic ataxia type 1, hypomagnesemia, paroxysmal kinesigenic dyskinesia, and epileptic encephalopathy, acting either by ER retention/aggregation of heterotetramers or by altered channel kinetics [#7, #13, #24, #34, #35]; neuron-restricted Kv1.1 loss alone is sufficient to drive epilepsy and brain-driven cardiorespiratory dysregulation underlying SUDEP [#26, #36].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established that Kv1.1 is itself a pore-forming subunit producing a functional delayed-rectifier K+ current and that it assembles selectively with Shaker-family subunits, defining the molecular building block.\",\n      \"evidence\": \"Stable mammalian expression with whole-cell patch clamp and pharmacology; in vitro translation, immunopurification, and pulse-chase of cotranslational assembly\",\n      \"pmids\": [\"7517498\", \"8126562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subunit stoichiometry in native tissue not resolved\", \"Glycosylation role left open for surface trafficking\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Defined the subcellular distribution of Kv1.1 to juxtaparanodes, synaptic terminals, somata, and dendrites, anchoring later excitability functions to specific neuronal compartments.\",\n      \"evidence\": \"Immunocytochemistry of mouse brain sections, contrasted with Kv1.2\",\n      \"pmids\": [\"8046438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish functional consequence of compartmental targeting\", \"Targeting/anchoring mechanism unknown\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identified lipid- and glycan-based modulation of voltage sensing, showing arachidonic acid and sialic acid residues tune Kv1.1 gating without altering surface expression.\",\n      \"evidence\": \"Patch clamp in Sf9 with iPLA2 and fatty acid application; expression in glycosylation-deficient CHO Lec cells with sialidase treatment\",\n      \"pmids\": [\"7852365\", \"8702582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological source of arachidonic acid in vivo not defined\", \"Whether sialylation state is regulated in neurons unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated through knockdown and knockout that Kv1.1 is required for hippocampal memory and for nociceptive/antinociceptive signaling, moving from biophysics to organismal function.\",\n      \"evidence\": \"Antisense knockdown with patch clamp and behavior; Kcna1 knockout mice with nociception assays\",\n      \"pmids\": [\"9114006\", \"9718989\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab behavioral findings\", \"Circuit-level basis of memory deficit not dissected\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Resolved the dominant-negative disease mechanism, showing truncated/EA1 subunits coassemble with wild-type and either trap heterotetramers in the ER or alter gating in defined stoichiometries.\",\n      \"evidence\": \"GH3/oocyte co-expression, double IP, subcellular fractionation, confocal imaging, TEA-tagging, tandem-linked subunits, single-channel analysis\",\n      \"pmids\": [\"9334228\", \"9526001\", \"10428758\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ER quality-control machinery retaining mutant channels not identified\", \"Genotype–phenotype severity correlation incomplete\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified protein partners and signaling inputs (Gβγ, PKC/Rho, Kvβ1, KCNE4) that regulate Kv1.1 current and inactivation, expanding the channel into a regulated signaling node.\",\n      \"evidence\": \"GST pulldown and Co-IP for Gβγ; phorbol ester/C3 toxin and mutagenesis for PKC; oocyte/HEK co-expression and confocal colocalization for KCNE4; enzymatic reconstitution for Kvβ1\",\n      \"pmids\": [\"10064591\", \"10409113\", \"18222921\", \"12944270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contexts engaging each modulator not established\", \"Direct structural interfaces largely undefined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Quantified Kv1.1's contribution to the low-threshold K+ current in auditory neurons and established its in vivo role in temporal precision, with partial subunit compensation by Kv1.2/Kv1.6.\",\n      \"evidence\": \"Patch clamp in Kcna1-null brainstem slices, DTX-K pharmacology, and in vivo single-unit recordings in VCN/MNTB\",\n      \"pmids\": [\"12611922\", \"14534254\", \"16672305\", \"11290530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of heteromeric compensation not fully resolved\", \"Contribution of accessory subunits in vivo unquantified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Mapped post-translational palmitoylation at C243 as a voltage-sensing modulator, linking membrane attachment of the S2-S3 linker to gating.\",\n      \"evidence\": \"[3H]palmitate labeling, mutagenesis, and patch clamp in Sf9 cells\",\n      \"pmids\": [\"15837928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Palmitoyl-transferase responsible not identified\", \"Dynamic regulation of palmitoylation in neurons unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established translational control of dendritic Kv1.1 by mTOR, later refined into a bidirectional mTOR–miR-129–HuD axis, explaining activity-dependent and disease-associated changes in channel abundance.\",\n      \"evidence\": \"Rapamycin/NMDA blockade with Kaede local-synthesis reporter; miR-129 reporters, HuD RIP, and competitive binding assays\",\n      \"pmids\": [\"17023663\", \"23836929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals setting mTOR tone in dendrites not defined\", \"Selectivity of miR-129/HuD for Kv1.1 vs other targets unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended Kv1.1 function beyond neurons to the kidney DCT, where it colocalizes with TRPM6 and a dominant-negative mutation causes hypomagnesemia by abolishing the favorable membrane potential for Mg2+ reabsorption.\",\n      \"evidence\": \"Positional cloning, HEK patch clamp with wild-type co-expression, kidney immunohistochemistry; systematic N255 mutagenesis with surface biotinylation\",\n      \"pmids\": [\"19307729\", \"19903818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DCT Kv1.1 is regulated by hormonal Mg2+ signals unknown\", \"Channel partners in renal epithelium beyond TRPM6 not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined Kv1.1's presynaptic and mechanosensory roles, showing it brakes neurotransmitter release and sets DRG mechanical thresholds, and connected it to the LGI1–ADAM23 presynaptic complex.\",\n      \"evidence\": \"MEA recordings and DTX-κ in Kcna1-null hippocampus; toxin profiling and dominant-negative transgenics in DRG with behavior; patient-IgG transfer with patch clamp and LTP\",\n      \"pmids\": [\"23466697\", \"23473320\", \"30346486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of Kv1.1 mechanosensitivity not structurally defined\", \"How LGI1–ADAM23 stabilizes presynaptic Kv1.1 mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated that neuron-restricted loss of Kv1.1 is sufficient to produce epilepsy and brain-driven cardiorespiratory dysregulation, localizing SUDEP-relevant phenotypes to the central nervous system.\",\n      \"evidence\": \"Synapsin1-Cre conditional Kcna1 knockout with EEG, ECG, plethysmography; earlier autonomic pharmacological dissection in global knockouts\",\n      \"pmids\": [\"31978607\", \"20392939\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific neuronal circuits driving lethal events not pinpointed\", \"Therapeutic reversibility not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse regulatory inputs (palmitoylation, PKA/PKC, Gβγ, mTOR-miR-129-HuD, RNA editing) are integrated in vivo to set Kv1.1 availability in specific compartments remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of compartment-specific regulation\", \"Interplay between transcriptional, translational, and post-translational control untested in native neurons\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 15, 24, 39]},\n      {\"term_id\": \"GO:0005216\", \"supporting_discovery_ids\": [0, 15]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 24, 31, 37]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6, 13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [31, 40]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [17, 29, 30, 43]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [24, 0]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 24, 34, 35, 36]}\n    ],\n    \"complexes\": [\"Kv1 (Shaker) channel tetramer\", \"Kv1.1/Kvβ1 channel complex\", \"Kv1.1/Kv1.2 heteromeric channel\"],\n    \"partners\": [\"KCNA2\", \"KCNA4\", \"KCNAB1\", \"KCNE4\", \"TRPM6\", \"ADAM23\", \"LGI1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}