{"gene":"KCNA2","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2005,"finding":"X-ray crystal structure of Kv1.2 at 2.9 Å resolution revealed that voltage sensors are essentially independent domains inside the membrane, that mechanical work is performed on the pore through S4-S5 linker helices which constrict or dilate the S6 inner helices, and that in the open conformation two of four conserved Arg residues on S4 face lipid and two are buried in the voltage sensor.","method":"X-ray crystallography (crystal structure determination)","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — landmark crystal structure with direct mechanistic interpretation, >800 citations","pmids":["16002579"],"is_preprint":false},{"year":1994,"finding":"Kv1.2 protein is localized to multiple distinct subcellular compartments in neurons including synaptic terminals, juxta-paranodal regions of myelinated axons, unmyelinated axons, and proximal dendrites, with differential distribution compared to Kv1.1, suggesting it participates in distinct heteromultimeric complexes in different subcellular domains.","method":"Immunocytochemistry and subcellular fractionation in mouse brain","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — direct localization by immunocytochemistry, replicated across brain regions, >300 citations","pmids":["8046438"],"is_preprint":false},{"year":1994,"finding":"Kv1.2 shows complex differential subcellular distribution in neurons: concentrated in dendrites of hippocampal/cortical pyramidal and Purkinje cells, but predominantly in nerve terminals of cerebellar basket cells, suggesting Kv1.2-containing channels play diverse functional roles depending on neuronal cell type and subcellular compartment.","method":"Combined in situ hybridization and immunocytochemistry in rat brain","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — direct subcellular localization with functional inference, >150 citations","pmids":["8158277"],"is_preprint":false},{"year":2003,"finding":"Kv1.2 homomers are responsible for two-thirds of presynaptic low-threshold K+ current at the calyx of Held, are located in the transition zone between axon and synaptic terminal, and suppress terminal hyperexcitability by limiting depolarizing after-potentials that would otherwise generate additional action potentials.","method":"Selective pharmacological blockade (tityustoxin-Kα and DTX-K) combined with current-clamp and paired pre/postsynaptic recordings in rat calyx of Held","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 — selective toxin dissection combined with functional electrophysiology, replicated with paired recordings, >130 citations","pmids":["12777451"],"is_preprint":false},{"year":1999,"finding":"Receptor protein tyrosine phosphatase alpha (RPTPalpha) co-immunoprecipitates with Kv1.2 in an m1 muscarinic receptor-dependent manner, directly binds N- and C-termini of Kv1.2 in vitro, and overexpression of RPTPalpha reverses tyrosine kinase-induced phosphorylation and suppression of Kv1.2 current, revealing a mechanism whereby GPCR-mediated Kv1.2 suppression depends on coordinate regulation of PTK and PTP activities.","method":"Co-immunoprecipitation, in vitro binding assays, Xenopus oocyte electrophysiology, biochemical phosphorylation analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including reciprocal co-IP, in vitro binding, and functional electrophysiology","pmids":["9878055"],"is_preprint":false},{"year":2000,"finding":"The Kv1.2 alpha-subunit mediates O2-sensitive K+ current in PC12 cells; anti-Kv1.2 antibody dialyzed intracellularly completely blocked the O2-sensitive current, and recombinant Kv1.2 expressed in Xenopus oocytes was inhibited by hypoxia, demonstrating Kv1.2 confers O2 sensitivity to this channel.","method":"Intracellular antibody blockade in patch clamp, Xenopus oocyte expression, Western blot","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 — direct intracellular antibody blockade plus recombinant expression, multiple orthogonal methods","pmids":["10790158"],"is_preprint":false},{"year":2002,"finding":"Kv1.2 associates with the actin-binding protein cortactin; the interaction maps to a 19-amino acid span in the Kv1.2 C-terminus; tyrosine phosphorylation of specific C-terminal tyrosines attenuates cortactin binding; M1 muscarinic receptor activation reduces cortactin-Kv1.2 interaction; and Kv1.2 mutants deficient in cortactin binding exhibit strongly attenuated ionic current, demonstrating a phosphorylation-dependent interaction with the actin cytoskeleton that regulates channel current.","method":"Co-immunoprecipitation, purified recombinant protein binding assays, immunocytochemistry, electrophysiology in HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — reconstituted direct binding with purified proteins, mutagenesis, and functional electrophysiology","pmids":["12151401"],"is_preprint":false},{"year":2007,"finding":"Cortactin directly regulates Kv1.2 endocytosis; pull-down assays confirmed direct Kv1.2-cortactin interaction that is reduced by tyrosine phosphorylation; FRET demonstrated in vivo interaction; cortactin's C-terminal tyrosines, fourth repeat actin-binding domain, and N-terminal Arp2/3-binding region are critical for Kv1.2 regulation, while cortactin's SH3 (dynamin-binding) domain is not required despite dynamin-dependent endocytosis.","method":"Recombinant pull-down, FRET, flow cytometry, cortactin gene replacement, site-directed mutagenesis","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including FRET, reconstituted pull-down, and mutagenesis with functional readouts","pmids":["17959782"],"is_preprint":false},{"year":2007,"finding":"C-terminal phosphorylation of Kv1.2 at pS440/pS441 (identified by tandem MS from rat, human, and mouse brain) is present only on post-ER/cell surface Kv1.2, not on newly synthesized ER-localized protein; elimination of these phosphorylation sites reduces cell surface expression and functional Kv1.2 channel expression; S449 phosphorylation regulates phosphorylation at S440/S441 and also affects surface expression.","method":"Tandem mass spectrometry phosphoproteomics, site-directed mutagenesis, cell surface biotinylation, electrophysiology","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1-2 — MS-identified in vivo sites confirmed by mutagenesis and functional trafficking assays across multiple species","pmids":["18056633"],"is_preprint":false},{"year":2007,"finding":"Secretin decreases cell-surface Kv1.2 levels in cerebellar slices by modulating Kv1.2 endocytic trafficking via adenylate cyclase/PKA pathway; this effect is mimicked by forskolin and blocked by AC or PKA inhibitors; Kv1.2 endocytosis occurs in basket cell axon terminals and Purkinje cell dendrites; secretin or Kv1.2 inhibition enhances eyeblink conditioning acquisition.","method":"Cell-surface protein biotinylation, cerebellar slice pharmacology, behavioral testing (eyeblink conditioning) in rat","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — biochemical trafficking assay + pharmacological dissection + behavioral consequence, multiple methods","pmids":["22764231"],"is_preprint":false},{"year":2007,"finding":"cAMP maintains Kv1.2 homeostasis through two distinct pathways: a PKA-dependent pathway that controls steady-state channel turnover (basal PKA inhibition elevates surface Kv1.2), and a PKA-independent pathway (elevated cAMP increases surface Kv1.2 by inhibiting endocytosis).","method":"Cell-surface biotinylation, pharmacological inhibitors of PKA and endocytosis, functional expression assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — clean biochemical and pharmacological dissection in single lab","pmids":["18003609"],"is_preprint":false},{"year":2003,"finding":"Kv1.2-containing channels underlie a slowly inactivating, low-threshold K+ current in striatal medium spiny neurons; toxin studies (alpha-DTX sensitive, but not DTX-K, agitoxin-2, or margatoxin) implicated Kv1.2 subunits; blockade of these channels reduced first-spike latency and increased discharge frequency from hyperpolarized membrane potentials, establishing a role in regulating state transitions and repetitive discharge.","method":"Pharmacological dissection with Kv1-selective toxins, whole-cell voltage/current clamp in acutely isolated neurons and slices, RT-PCR","journal":"Journal of neurophysiology","confidence":"High","confidence_rationale":"Tier 2 — selective pharmacological dissection with multiple toxins + functional electrophysiology in native cells and slices","pmids":["13679409"],"is_preprint":false},{"year":2013,"finding":"Cocaine exposure triggers a sigma-1 receptor (Sig-1R)-dependent upregulation of D-type K+ current in nucleus accumbens neurons through a persistent protein-protein association between Sig-1R and Kv1.2 channels, accompanied by redistribution of both proteins from intracellular compartments to the plasma membrane, resulting in neuronal hypoactivity.","method":"Co-immunoprecipitation, ex vivo and in vitro electrophysiology, subcellular fractionation/trafficking assays, behavioral studies","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, subcellular redistribution assays, and electrophysiological validation with behavioral consequence, >170 citations","pmids":["23332758"],"is_preprint":false},{"year":2013,"finding":"A lncRNA antisense to Kcna2 (Kcna2 antisense RNA) is induced by nerve injury in DRG via activation of myeloid zinc finger protein 1 (MZF1, which binds the antisense RNA gene promoter); this lncRNA silences Kcna2 expression by an antisense mechanism, reduces total voltage-gated K+ current, increases DRG neuron excitability, and produces neuropathic pain symptoms.","method":"Chromatin immunoprecipitation (ChIP), reporter assay, antisense RNA overexpression/knockdown, patch-clamp electrophysiology, behavioral pain testing in rats","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods: ChIP, functional electrophysiology, and behavioral phenotype; highly cited","pmids":["23792947"],"is_preprint":false},{"year":2015,"finding":"De novo KCNA2 mutations cause epileptic encephalopathy through two opposite mechanisms: loss-of-function mutations (dominant-negative current amplitude reduction) produce focal seizures and multifocal epileptiform discharges, while gain-of-function mutations (permanently open channels with hyperpolarizing shift of voltage-dependent activation) produce more severe epilepsy and ataxia, establishing genotype-phenotype correlations.","method":"Next-generation sequencing, functional studies in Xenopus oocytes (two-microelectrode voltage clamp), site-directed mutagenesis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — functional characterization in expression system with electrophysiology and multiple mutations, >200 citations","pmids":["25751627"],"is_preprint":false},{"year":2017,"finding":"DNMT3a methylates the Kcna2 promoter region in injured DRG neurons (induced via activation of transcription factor Oct1), silencing Kcna2 expression; blocking DNMT3a prevents promoter methylation, rescues Kcna2 expression and Kv current, reduces neuronal excitability, and attenuates neuropathic pain.","method":"ChIP, bisulfite sequencing, reporter assays, DRG microinjection of virus expressing DNMT3a or shRNA, patch-clamp electrophysiology, behavioral pain testing","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including ChIP, bisulfite sequencing, electrophysiology, and behavioral phenotyping","pmids":["28270689"],"is_preprint":false},{"year":2016,"finding":"G9a (euchromatic histone-lysine N-methyltransferase 2) contributes to nerve injury-induced downregulation of Kcna2 in DRG; blocking G9a increase rescues Kcna2 mRNA and protein expression; mimicking G9a increase reduces Kcna2, reduces Kv current, increases DRG neuron excitability, and produces neuropathic pain.","method":"Western blot, qRT-PCR, intrathecal siRNA injection, patch-clamp electrophysiology, behavioral pain testing in rats","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function and gain-of-function with electrophysiological and behavioral readouts, single lab","pmids":["27874088"],"is_preprint":false},{"year":2019,"finding":"DNMT1 acts as a de novo methyltransferase in injured DRG neurons (upregulated via CREB-mediated transcriptional activation of Dnmt1); it methylates the Kcna2 promoter and 5'-UTR, represses Kcna2 expression, increases neuronal excitability, and contributes to neuropathic pain genesis.","method":"ChIP, bisulfite sequencing, DRG microinjection of siRNA/AAV, patch-clamp electrophysiology, behavioral pain testing in mice","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — ChIP, bisulfite sequencing, functional electrophysiology, and behavioral phenotyping with mechanistic pathway defined","pmids":["31182635"],"is_preprint":false},{"year":2011,"finding":"D2 dopamine autoreceptor (D2-AR) activation increases Kv1.2 currents through Gβγ subunit signaling; D2-AR and Kv1.2-containing channels physically associate (co-immunoprecipitation in striatal tissue); Kv1.2-specific blockade or Kv1.2 knockout attenuates D2-AR-mediated inhibition of axonal dopamine overflow, demonstrating Kv1.2 as a downstream effector of D2-AR in nigrostriatal DA release regulation.","method":"Fast scan cyclic voltammetry, Kv1.2 knockout mice, selective pharmacological blockade, co-immunoprecipitation, K+ current recordings in co-transfected cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods: KO mice, selective blocker, co-IP, and electrophysiology","pmids":["21233214"],"is_preprint":false},{"year":2009,"finding":"PKA phosphorylates Kv1.2 specifically at Ser-449 (confirmed by in vitro phosphorylation, MALDI-TOF MS, MS/MS, and in situ phosphorylation in HEK293 cells); PKA-induced phosphorylation at Ser-449 increases Kv1.2 current amplitude, identified as a molecular mechanism for vasodilatory agonist modulation of Kv1 channels via PKA.","method":"In vitro phosphorylation, MALDI-TOF MS/MS, site-directed mutagenesis, whole-cell and inside-out patch clamp electrophysiology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay + MS confirmation + mutagenesis + functional electrophysiology","pmids":["19389710"],"is_preprint":false},{"year":2007,"finding":"Glycosylation state of Kv1.2 affects trafficking, gating, and action potentials: preventing N-glycosylation decreases cell surface expression ~40% via increased ER retention (rescued by Kv1.4 but not Kvβ2); increasing glycosylation shifts V(1/2) negatively and increases activation kinetics; decreasing glycosylation has opposite effects consistent with a surface potential mechanism for activation but a conformational mechanism for deactivation.","method":"Site-directed mutagenesis to alter glycosylation sites, Western blot, immunocytochemistry, whole-cell patch clamp, computational action potential simulation","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis + trafficking + electrophysiology in single study","pmids":["17324383"],"is_preprint":false},{"year":2016,"finding":"N-linked glycosylation of Kv1.2 is required for forward trafficking to the cell membrane; both wild-type and non-glycosylated Kv1.2 are internalized at comparable rates, but non-glycosylated channels are degraded faster after internalization; removal of sialic acids from cell-surface Kv1.2 also increases degradation of internalized channels.","method":"Site-directed mutagenesis, cell surface biotinylation, glycosidase treatment, pulse-chase experiments in COS-7 cells and hippocampal neurons","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis and biochemical trafficking assays with multiple orthogonal approaches","pmids":["27377235"],"is_preprint":false},{"year":2007,"finding":"Kv1.2 activation gating is bimodal ('fast' and 'slow' modes); introduction of a positive charge at or around threonine 252 in the S2-S3 linker abolishes 'slow' activation gating; cytoplasm dialysis or patch excision switches gating from slow to fast, implicating cytoplasmic regulators in the gating mode switch.","method":"Chimeric channel construction, site-directed mutagenesis, whole-cell and excised patch-clamp electrophysiology in HEK293 cells","journal":"Biophysical journal","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis with functional electrophysiology defining gating switch residue","pmids":["17766348"],"is_preprint":false},{"year":2013,"finding":"A conditioning train of action potentials at 10 Hz causes long-term potentiation of intrinsic excitability (LTP-IE) in CA3 pyramidal cells mediated by internalization of Kv1.2 channels; LTP-IE was absent in Kv1.2 knockout mice, required intact distal apical dendrites, back-propagating APs, dendritic Ca2+ signaling, and protein tyrosine kinase activation; endocytosis inhibition blocked LTP-IE.","method":"Kv1.2 knockout mice, whole-cell patch clamp, endocytosis inhibition, PTK inhibition, dendritic ablation in hippocampal slices","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 — KO mice combined with pharmacological dissection and functional electrophysiology with defined mechanism","pmids":["23981714"],"is_preprint":false},{"year":2015,"finding":"Kv1.2 mediates MF-induced heterosynaptic LTP of perforant path inputs in CA3 pyramidal cells; Kv1.2 expression is polarized to distal apical dendrites; downregulation of Kv1.2 preferentially enhances distal PP-evoked EPSPs; this enhancement requires activation of dendritic Na+ channels, and its threshold is lowered by Kv1.2 downregulation.","method":"Whole-cell patch clamp in hippocampal slices, immunohistochemistry, compartmental simulation, tetrodotoxin pharmacology, Kv1.2 KO/knockdown","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 — electrophysiology with KO and pharmacological validation, single lab","pmids":["26047212"],"is_preprint":false},{"year":2018,"finding":"Slc7a5 (a neutral amino acid transporter) interacts with Kv1.2 (identified by mass spectrometry of Kv1.2 multi-protein complexes), reduces total Kv1.2 protein, and dramatically hyperpolarizes voltage-dependence of activation by -47 mV; Slc3a2 (binding partner of Slc7a5) attenuates these effects; neurodevelopmental delay-linked Slc7a5 mutations show localization defects and attenuated effects on Kv1.2.","method":"Mass spectrometry interactome, co-expression in Xenopus oocytes, two-electrode voltage clamp, site-directed mutagenesis, confocal imaging","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — MS-identified interaction confirmed by functional expression and mutagenesis with multiple orthogonal methods","pmids":["30356053"],"is_preprint":false},{"year":2015,"finding":"Kv1.2 exhibits use-dependent activation during trains of brief depolarizations (enabled by prepulse potentiation); this property is unique to Kv1.2 among Kv1 channels and is conferred even by a single Kv1.2 subunit in heteromeric channel complexes; use-dependent activation is observed in both mammalian cell lines and primary hippocampal neurons.","method":"Voltage-clamp electrophysiology in mammalian cells, primary hippocampal neuron cultures, heteromeric channel co-expression","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — functional electrophysiology in multiple cell types with heteromeric channel validation","pmids":["25716850"],"is_preprint":false},{"year":2019,"finding":"Sigma-1 receptor (Sig-1R) interacts with Kv1.2 at baseline to influence bimodal activation gating; ligand activation of Sig-1R modulates Kv1.2 current amplitude; these effects are abolished by auxiliary subunit Kvβ2 (which occludes the Sig-1R interaction site) and by ALS16-linked Sig-1R mutation E102Q.","method":"Co-expression in HEK293 cells, whole-cell patch clamp, site-directed mutagenesis, pharmacological Sig-1R ligand activation","journal":"Physiological reports","confidence":"Medium","confidence_rationale":"Tier 3 — functional co-expression study with mutagenesis but limited biochemical validation of direct interaction","pmids":["31222975"],"is_preprint":false},{"year":2001,"finding":"Kv1.2 and Kv1.5 form heteromultimeric channels in rabbit portal vein myocytes; 4-AP block of native vascular K(DR) shows voltage-dependent characteristics matching Kv1.2 homomers and Kv1.2/Kv1.5 heterotetramers but not Kv1.5 homomers; charybdotoxin insensitivity of native channels distinguishes them from Kv1.2 homotetramers.","method":"Patch clamp electrophysiology, tandem-linked subunit expression in mammalian cells, pharmacological characterization","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 — functional characterization of native and recombinant channels with pharmacological dissection","pmids":["11717161"],"is_preprint":false},{"year":2007,"finding":"Molecular dynamics simulations of Kv1.2 in lipid membrane show the voltage-sensing domains undergo important lateral fluctuations consistent with their modular nature; S4 arginines R294 and R297 adopt interfacial positions interacting with water and lipid headgroups, while R300 and R303 interact predominantly with water and E226 in S2; the transmembrane potential is focused over the outer half of the membrane in the arginine-rich region of S4.","method":"All-atom molecular dynamics simulation with continuum electrostatic computations","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 1 computational — MD simulation validated against structural data, no direct mutagenesis confirmation","pmids":["17704179"],"is_preprint":false},{"year":2008,"finding":"Kv1.2 and the paddle chimera channel (with Kv2.1 voltage sensor paddle transferred to Kv1.2) produced in Pichia yeast are functional in planar lipid bilayers with properties qualitatively similar to Shaker K+ channel; several functional properties of Kv1.2 are distinct from previously reported Kv1.2 in other systems.","method":"Planar lipid bilayer electrophysiology, yeast expression system","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 — reconstitution in planar lipid bilayers with electrophysiological characterization","pmids":["18638484"],"is_preprint":false},{"year":2025,"finding":"CryoEM structures of Kv1.2 in open (3.2 Å), C-type inactivated (2.5 Å), α-dendrotoxin-blocked (3.2 Å), and Na+-bound (2.9 Å) states reveal: toxin lysine penetrates the selectivity filter disrupting the outermost ion-binding site; in Na+ solution the selectivity filter remains intact with ion density at each binding site rather than collapsing; C-type inactivated W366F in Na+ shows highly variable protein conformation.","method":"Single-particle cryoEM structure determination at near-atomic resolution","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 — near-atomic resolution cryoEM structures across multiple functional states with direct mechanistic interpretation","pmids":["39945513"],"is_preprint":false},{"year":2015,"finding":"Kv1.2 gating charge measured directly is ~10 elementary charges, ~25% less than Shaker; neutralization of R1 in Kv1.2 S4 decreases voltage sensitivity to ~50% of wild-type, whereas subsequent arginines have much smaller effects (contrasting with Shaker), suggesting the voltage-sensing domain aqueous crevice septum in Kv1.2 may be thicker than in Shaker.","method":"Two-electrode voltage clamp in Xenopus oocytes, site-directed mutagenesis of S4 arginines, gating current measurement","journal":"The Journal of general physiology","confidence":"Medium","confidence_rationale":"Tier 1 — direct gating charge measurement with systematic mutagenesis","pmids":["25779871"],"is_preprint":false},{"year":2018,"finding":"MBD1 (methyl-CpG-binding domain protein 1) represses Kcna2 gene expression in DRG neurons by recruiting DNMT3a to the Kcna2 promoter; DRG MBD1 deficiency blunts nerve injury-induced pain hypersensitivity and reduces acute pain responses; DRG overexpression of MBD1 produces pain hypersensitivity and restores acute pain in MBD1-deficient mice.","method":"ChIP for MBD1 and DNMT3a at Kcna2 promoter, DRG-specific knockout/overexpression, behavioral pain testing in mice","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-defined molecular mechanism with loss- and gain-of-function behavioral phenotypes","pmids":["30266739"],"is_preprint":false},{"year":2023,"finding":"Transcription factor EBF1 directly binds the Kcna2 gene promoter and activates its transcriptional activity in DRG neurons; nerve injury reduces EBF1 binding to the Kcna2 promoter; EBF1 overexpression reverses CCI-induced Kv1.2 downregulation; EBF1 knockdown reduces Kv1.2 expression and produces pain hypersensitivity.","method":"ChIP, reporter assay (Kcna2 promoter-luciferase), AAV-mediated DRG overexpression/knockdown, behavioral pain testing in mice","journal":"Translational research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter assay define direct transcriptional activation, with in vivo functional validation","pmids":["37607607"],"is_preprint":false},{"year":2020,"finding":"Slc7a5-induced suppression of Kv1.2 current and protein expression is attenuated by Kvβ1.2 co-transfection; however, gating effects of Slc7a5 (disinhibition and hyperpolarizing shift in activation) persist alongside Kvβ-mediated inactivation; Slc7a5 modifies Kvβ-induced inactivation including accelerated inactivation, hyperpolarizing shift of steady-state inactivation, and delayed recovery from inactivation.","method":"Co-transfection in Xenopus oocytes, two-electrode voltage clamp, Kv1.2/Kvβ/Slc7a5 triple co-expression","journal":"The Journal of general physiology","confidence":"Medium","confidence_rationale":"Tier 2 — systematic electrophysiological dissection of three-way regulatory interaction","pmids":["32311044"],"is_preprint":false},{"year":2007,"finding":"Kv1.2 knockout mice have significantly less NREM sleep (-23%) and more waking (+21%) than wild-type littermates at P17, with increased number of waking episodes but no change in REM sleep, establishing that Kv1.2 regulates NREM sleep in mammals.","method":"EEG/EMG continuous recording, video monitoring, sleep scoring in Kcna2 knockout mice","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct genetic knockout with defined EEG/behavioral phenotype","pmids":["17925011"],"is_preprint":false},{"year":2008,"finding":"Kv1.2 is expressed in microglia; blockade of Kv1.2 with tityustoxin-Kα partially recovers intracellular K+ concentration and reduces IL-1β and TNF-α mRNA/protein expression and intracellular ROS production in hypoxia/LPS/ATP-treated microglia, suggesting Kv1.2 regulates microglial proinflammatory cytokine production by modulating intracellular K+ concentration.","method":"Pharmacological blockade, quantitative RT-PCR, Western blot, immunofluorescence, intracellular K+ measurement in rat brain and primary microglia","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 3 — pharmacological loss-of-function with molecular readouts, single lab","pmids":["18627436"],"is_preprint":false},{"year":1999,"finding":"Kv1.2 is resistant to acidic pH while Kv1.5 shows enhanced C-type inactivation at acidic pH; a histidine residue in the third extracellular loop of Kv1.5 (H452) accounts for this difference; mutation of H452 to glutamine in Kv1.5 abolishes pH-dependent inactivation, revealing H452 as a pH sensor for C-type inactivation.","method":"Two-electrode voltage clamp and cell-attached patch clamp in Xenopus oocytes, site-directed mutagenesis","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 1 — mutagenesis identifies molecular determinant of pH sensitivity with functional validation; relevant to Kv1.2 as the resistant channel","pmids":["10220559"],"is_preprint":false},{"year":2024,"finding":"BCAA deficiency activates LAT1 (L-type amino acid transporter 1, i.e. Slc7a5) expression through ATF4, and upregulated LAT1 reduces Kv1.2 localization to the cell membrane, inhibiting Kv1.2 channels and increasing DRG neuronal excitability to cause neuropathic pain in diabetic models.","method":"RNA sequencing, label-free quantitative proteomics, western blot, patch-clamp electrophysiology, pharmacological LAT1 inhibition in mouse DRG and HFD/STZ and db/db mouse models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — multi-omics plus electrophysiology plus pharmacological validation in multiple in vivo models","pmids":["38946582"],"is_preprint":false},{"year":2017,"finding":"HDAC2, but not HDAC1, regulates Kv1.2 expression in DRG neurons; Kv1.2 co-localizes with HDAC2 in NF200-positive large neurons; HDAC2 siRNA relieves mechanical/thermal hypersensitivity in CCI rats and upregulates Kv1.2, whereas HDAC1 siRNA has no effect on Kv1.2; HDAC2 siRNA in PC12 cells also upregulates Kv1.2.","method":"Double-label immunofluorescence, intrathecal siRNA injection, HDAC inhibitor treatment, western blot, qRT-PCR in CCI rats","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 — siRNA knockdown with molecular and behavioral readouts but no direct chromatin/promoter assay for HDAC2 at Kcna2","pmids":["31022463"],"is_preprint":false}],"current_model":"Kv1.2 is a voltage-gated potassium channel whose crystal and cryoEM structures reveal independent voltage-sensing domains that transduce membrane voltage through S4-S5 linker helices to gate the pore; it is regulated by a complex array of post-translational modifications (tyrosine phosphorylation by PTKs reversed by RPTPα, PKA-mediated phosphorylation at Ser-449/Ser-440/Ser-441, N-glycosylation) that control its trafficking to and from the plasma membrane, and by protein interactions (with cortactin, Sig-1R, Kvβ subunits, and Slc7a5) that modulate its gating and surface expression; epigenetic silencing of Kcna2 (via DNMT3a, DNMT1, G9a, MBD1, and a natural antisense lncRNA) in primary sensory neurons after nerve injury reduces Kv1.2-mediated K+ current, increases neuronal excitability, and drives neuropathic pain, while presynaptically, Kv1.2 suppresses terminal hyperexcitability and mediates D2 autoreceptor regulation of dopamine release."},"narrative":{"teleology":[{"year":1994,"claim":"Establishing where Kv1.2 protein resides in the nervous system was prerequisite to understanding its functional roles; immunolocalization revealed differential subcellular targeting—synaptic terminals, juxta-paranodes, dendrites—varying by neuronal type, implying participation in distinct heteromultimeric complexes at each site.","evidence":"Immunocytochemistry and subcellular fractionation across mouse and rat brain regions","pmids":["8046438","8158277"],"confidence":"High","gaps":["Identity of heteromultimeric partners at each subcellular site was not determined","Mechanism directing polarized trafficking to specific compartments was unknown"]},{"year":1999,"claim":"The question of how GPCR signaling suppresses Kv1.2 was answered by showing that RPTPα directly binds Kv1.2, counteracts tyrosine-kinase-mediated phosphorylation and current suppression, and is recruited to Kv1.2 in an m1 muscarinic receptor–dependent manner, establishing a phosphorylation-based regulatory axis.","evidence":"Co-immunoprecipitation, in vitro binding, Xenopus oocyte electrophysiology","pmids":["9878055"],"confidence":"High","gaps":["Identity of the tyrosine kinase phosphorylating Kv1.2 in this pathway was not established","Specific phosphorylated tyrosine residues on Kv1.2 were not mapped"]},{"year":2002,"claim":"Discovery that cortactin physically links Kv1.2 to the actin cytoskeleton—and that tyrosine phosphorylation disrupts this interaction—resolved how cytoskeletal association controls channel current magnitude and laid the groundwork for understanding phosphorylation-triggered endocytosis.","evidence":"Purified recombinant binding assays, co-immunoprecipitation, mutagenesis, electrophysiology in HEK293 cells; later confirmed by FRET, cortactin domain mutagenesis, and endocytosis assays","pmids":["12151401","17959782"],"confidence":"High","gaps":["Structural basis of the cortactin–Kv1.2 interface was not determined","Role of Arp2/3-mediated actin remodeling versus simple anchoring in endocytosis was not fully separated"]},{"year":2003,"claim":"Selective toxin dissection at the calyx of Held and in striatal neurons demonstrated that Kv1.2 homomers carry the majority of low-threshold presynaptic K⁺ current and suppress terminal hyperexcitability, establishing a specific physiological function for Kv1.2 at defined synapses.","evidence":"Tityustoxin-Kα and DTX-K pharmacology combined with paired pre/postsynaptic recordings (calyx) and whole-cell recordings (striatal neurons)","pmids":["12777451","13679409"],"confidence":"High","gaps":["Contribution of heteromeric Kv1.2-containing channels versus homomers at these synapses was only partially resolved","Mechanisms regulating Kv1.2 density at the presynaptic transition zone were unknown"]},{"year":2005,"claim":"The 2.9 Å crystal structure of Kv1.2 resolved a long-standing debate about voltage-sensor topology by showing voltage-sensing domains as modular peripheral units connected to the pore through S4–S5 linker helices, with conserved S4 arginines positioned at the protein–lipid interface.","evidence":"X-ray crystallography of full-length Kv1.2","pmids":["16002579"],"confidence":"High","gaps":["Only the open-state structure was captured; closed- and inactivated-state conformations were unknown","Lipid interactions were modeled but not directly resolved"]},{"year":2007,"claim":"A cluster of discoveries defined how post-translational modifications control Kv1.2 trafficking: C-terminal phosphorylation at S440/S441 (identified by MS across three species) marks post-ER channels for surface delivery; N-glycosylation promotes ER exit and modulates gating; PKA and cAMP pathways bidirectionally regulate surface expression through endocytosis and turnover.","evidence":"Tandem MS phosphoproteomics, site-directed mutagenesis, cell-surface biotinylation, glycosylation-site mutagenesis, pharmacological dissection of cAMP/PKA pathways","pmids":["18056633","17324383","18003609"],"confidence":"High","gaps":["The kinase responsible for S440/S441 phosphorylation was not identified","How glycosylation and phosphorylation signals are coordinated was not addressed"]},{"year":2007,"claim":"Identification of bimodal (fast/slow) activation gating unique to Kv1.2 and mapping of the gating-mode switch to a charge at T252 in the S2–S3 linker revealed an intrinsic regulatory mechanism modifiable by cytoplasmic factors, distinguishing Kv1.2 from other Kv1 channels.","evidence":"Chimeric channel construction, site-directed mutagenesis, excised-patch electrophysiology in HEK293 cells","pmids":["17766348"],"confidence":"High","gaps":["The identity of the endogenous cytoplasmic regulator switching gating mode was not determined","Structural basis of the two gating conformations was not resolved"]},{"year":2009,"claim":"PKA phosphorylation of Kv1.2 was mapped to Ser-449 by mass spectrometry and mutagenesis, with functional electrophysiology showing this modification increases current amplitude, providing a molecular mechanism for vasodilatory agonist modulation of Kv1 channels.","evidence":"In vitro kinase assay, MALDI-TOF MS/MS, site-directed mutagenesis, whole-cell and inside-out patch clamp","pmids":["19389710"],"confidence":"High","gaps":["Whether S449 phosphorylation operates in vascular smooth muscle in vivo was not confirmed","Cross-talk between S449 and the S440/S441 phosphorylation cluster was only partially explored"]},{"year":2011,"claim":"D2 dopamine autoreceptor activation was shown to increase Kv1.2 current via Gβγ signaling, with physical association between D2-AR and Kv1.2 in striatum; Kv1.2 KO attenuated D2-AR-mediated inhibition of dopamine overflow, establishing Kv1.2 as a downstream effector of presynaptic dopamine autoreceptor signaling.","evidence":"Fast-scan cyclic voltammetry in Kv1.2 KO mice, co-immunoprecipitation from striatal tissue, selective pharmacological blockade","pmids":["21233214"],"confidence":"High","gaps":["Whether Gβγ directly binds Kv1.2 or acts through an intermediary was not resolved","Contribution of heteromeric Kv1.2 complexes versus homomers in dopamine terminals was not dissected"]},{"year":2013,"claim":"Two parallel discoveries connected Kv1.2 downregulation to neuropathic pain and synaptic plasticity: a nerve injury–induced antisense lncRNA (driven by MZF1) silences Kcna2 in DRG to increase excitability and produce pain; activity-dependent Kv1.2 endocytosis in CA3 dendrites mediates long-term potentiation of intrinsic excitability.","evidence":"ChIP, antisense RNA overexpression/knockdown, patch-clamp and behavioral pain testing (neuropathic pain); Kv1.2 KO mice, endocytosis inhibition, PTK blockade in hippocampal slices (LTP-IE)","pmids":["23792947","23981714"],"confidence":"High","gaps":["Mechanism by which the antisense lncRNA degrades or silences Kcna2 mRNA at a molecular level was not fully elucidated","Whether LTP-IE-associated Kv1.2 endocytosis uses the same cortactin/tyrosine-phosphorylation pathway was not confirmed"]},{"year":2013,"claim":"Sigma-1 receptor was found to form a persistent protein complex with Kv1.2, promoting its redistribution to the plasma membrane and upregulating D-type K⁺ current in nucleus accumbens after cocaine exposure, establishing a Sig-1R–Kv1.2 axis in addiction-related neuronal hypoactivity.","evidence":"Co-immunoprecipitation, subcellular fractionation, ex vivo electrophysiology, behavioral studies in cocaine-exposed rats","pmids":["23332758"],"confidence":"High","gaps":["The Sig-1R binding site on Kv1.2 was not mapped","Whether Kvβ subunits occlude Sig-1R interaction in vivo (as later suggested in heterologous cells) was not tested in native tissue"]},{"year":2015,"claim":"De novo KCNA2 mutations were shown to cause epileptic encephalopathy through two mechanistically opposite routes—loss-of-function (dominant-negative) and gain-of-function (constitutively open)—with distinct clinical presentations, establishing genotype-phenotype correlations for KCNA2 channelopathy.","evidence":"Next-generation sequencing of patient cohorts, Xenopus oocyte voltage-clamp functional characterization","pmids":["25751627"],"confidence":"High","gaps":["Neuron-type-specific consequences of each mutation class were not characterized","Whether gain-of-function mutations alter Kv1.2 heteromultimerization was not tested"]},{"year":2017,"claim":"The epigenetic silencing pathway was extended: DNMT3a (recruited by Oct1 and MBD1) and later DNMT1 (activated by CREB) were shown to directly methylate the Kcna2 promoter in injured DRG neurons, suppressing Kv1.2 and driving neuropathic pain; G9a and HDAC2 also contribute to injury-induced Kcna2 repression.","evidence":"ChIP, bisulfite sequencing, reporter assays, viral overexpression/knockdown, siRNA, electrophysiology, behavioral pain testing in rodent models","pmids":["28270689","31182635","27874088","31022463"],"confidence":"High","gaps":["Hierarchical ordering of DNMT3a, DNMT1, G9a, and HDAC2 contributions was not determined","Whether these epigenetic modifications are reversible after nerve regeneration was not addressed"]},{"year":2018,"claim":"Slc7a5 (LAT1) was identified as a novel Kv1.2 interactor that dramatically hyperpolarizes voltage-dependent activation by ~47 mV and reduces total protein levels, with Kvβ and Slc3a2 providing counterbalancing modulation; this interaction has pathophysiological relevance in diabetic neuropathic pain where BCAA deficiency upregulates LAT1.","evidence":"Mass spectrometry interactome, co-expression electrophysiology, mutagenesis in Xenopus oocytes; RNA-seq, proteomics, and pharmacological LAT1 inhibition in DRG and diabetic mouse models","pmids":["30356053","32311044","38946582"],"confidence":"High","gaps":["Structural basis of the Slc7a5–Kv1.2 interaction is unknown","Stoichiometry of Slc7a5 modulation of native neuronal Kv1.2 complexes is uncharacterized"]},{"year":2025,"claim":"CryoEM structures in open, C-type inactivated, toxin-blocked, and Na⁺-bound states resolved how α-dendrotoxin blocks by inserting a lysine into the outermost selectivity filter site and showed the selectivity filter remains structurally intact in Na⁺ rather than collapsing, revising models of ion selectivity and C-type inactivation.","evidence":"Single-particle cryoEM at 2.5–3.2 Å resolution across four functional states","pmids":["39945513"],"confidence":"High","gaps":["Resting/closed-state structure has not been captured","Lipid-dependent modulation of the selectivity filter in native membranes was not addressed"]},{"year":null,"claim":"Key unresolved questions include the structural basis of bimodal gating and its endogenous cytoplasmic regulator, the resting-state conformation of the voltage sensor, the hierarchical organization of multiple epigenetic silencing pathways converging on Kcna2, and how heteromultimeric assembly with other Kv1 subunits determines subcellular targeting and functional diversity.","evidence":"","pmids":[],"confidence":"Low","gaps":["No resting-state Kv1.2 structure exists","Identity of the cytoplasmic factor switching bimodal gating is unknown","Whether therapeutic reversal of Kcna2 epigenetic silencing can treat neuropathic pain is untested in humans"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,3,5,11,14,31]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,8,12,21]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[8,20]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[6,7]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,2,3,11,13,14,18,23,24]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,9,12,18,19]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,3,5,14,31]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[7,8,9,20,21]}],"complexes":[],"partners":["PTPRA","CTTN","SIGMAR1","SLC7A5","DRD2","MBD1","DNMT3A"],"other_free_text":[]},"mechanistic_narrative":"KCNA2 encodes Kv1.2, a voltage-gated potassium channel that functions as a central regulator of neuronal excitability across diverse brain circuits, controlling presynaptic terminal firing fidelity, dendritic integration, intrinsic plasticity, dopaminergic neurotransmission, and sleep architecture. Structural studies reveal that independent voltage-sensing domains transduce membrane potential changes through S4–S5 linker helices to gate the pore, with gating charge contributed predominantly by the outermost S4 arginine and a unique bimodal (fast/slow) activation property conferred by residues in the S2–S3 linker [PMID:16002579, PMID:17766348, PMID:39945513]. Channel surface expression is dynamically regulated by a convergent set of post-translational mechanisms—tyrosine phosphorylation (modulated by RPTPα and cortactin interaction with the cytoskeleton), PKA phosphorylation at Ser-449/Ser-440/Ser-441, N-glycosylation-dependent ER export, and interactions with Slc7a5 and sigma-1 receptor—that collectively tune Kv1.2-mediated K⁺ current amplitude through endocytic trafficking and gating modulation [PMID:9878055, PMID:12151401, PMID:18056633, PMID:19389710, PMID:30356053, PMID:23332758]. De novo KCNA2 mutations cause epileptic encephalopathy through either loss-of-function (dominant-negative current reduction) or gain-of-function (constitutively open channels) mechanisms [PMID:25751627], and nerve injury–induced epigenetic silencing of Kcna2 by DNMT3a, DNMT1, G9a, MBD1, and a natural antisense lncRNA in dorsal root ganglion neurons reduces Kv1.2 current, increases excitability, and drives neuropathic pain [PMID:23792947, PMID:28270689, PMID:31182635]."},"prefetch_data":{"uniprot":{"accession":"P16389","full_name":"Potassium voltage-gated channel subfamily A member 2","aliases":["NGK1","Voltage-gated K(+) channel HuKIV","Voltage-gated potassium channel HBK5","Voltage-gated potassium channel subunit Kv1.2"],"length_aa":499,"mass_kda":56.7,"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 cardiovascular system. Prevents aberrant action potential firing and regulates neuronal output. 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:11211111, PubMed:19912772, PubMed:23769686, PubMed:8495559). 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:20220134, PubMed:8495559). 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. 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 KCNA2 forms a delayed-rectifier potassium channel that opens in response to membrane depolarization, followed by slow spontaneous channel closure (PubMed:19912772, PubMed:23769686). In contrast, a heteromultimer formed by KCNA2 and KCNA4 shows rapid inactivation (PubMed:8495559). Regulates neuronal excitability and plays a role as pacemaker in the regulation of neuronal action potentials (By similarity). KCNA2-containing channels play a presynaptic role and prevent hyperexcitability and aberrant action potential firing (By similarity). Response to toxins that are selective for KCNA2-containing potassium channels suggests that in Purkinje cells, dendritic subthreshold KCNA2-containing potassium channels prevent random spontaneous calcium spikes, suppressing dendritic hyperexcitability without hindering the generation of somatic action potentials, and thereby play an important role in motor coordination (By similarity). Plays a role in the induction of long-term potentiation of neuron excitability in the CA3 layer of the hippocampus (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) (By similarity). Contributes to the regulation of the axonal release of the neurotransmitter dopamine (By similarity). Reduced KCNA2 expression plays a role in the perception of neuropathic pain after peripheral nerve injury, but not acute pain (By similarity). Plays a role in the regulation of the time spent in non-rapid eye movement (NREM) sleep (By similarity)","subcellular_location":"Cell membrane; Membrane; Cell projection, axon; Synapse; Endoplasmic reticulum membrane; Cell projection, lamellipodium membrane; Synapse, synaptosome; Presynaptic cell membrane; Cell projection, dendrite; Cell junction, paranodal septate junction","url":"https://www.uniprot.org/uniprotkb/P16389/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KCNA2","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KCNA2","total_profiled":1310},"omim":[{"mim_id":"619295","title":"ZDHHC PALMITOYLTRANSFERASE 14; ZDHHC14","url":"https://www.omim.org/entry/619295"},{"mim_id":"616366","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 32; DEE32","url":"https://www.omim.org/entry/616366"},{"mim_id":"611925","title":"GAP JUNCTION PROTEIN, GAMMA-3; GJC3","url":"https://www.omim.org/entry/611925"},{"mim_id":"609743","title":"CELL ADHESION MOLECULE 3; CADM3","url":"https://www.omim.org/entry/609743"},{"mim_id":"608302","title":"LEUCINE-RICH GENE, GLIOMA-INACTIVATED, 3; LGI3","url":"https://www.omim.org/entry/608302"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":33.6},{"tissue":"retina","ntpm":8.9}],"url":"https://www.proteinatlas.org/search/KCNA2"},"hgnc":{"alias_symbol":["Kv1.2","HK4"],"prev_symbol":[]},"alphafold":{"accession":"P16389","domains":[{"cath_id":"3.30.710.10","chopping":"31-129","consensus_level":"high","plddt":95.1002,"start":31,"end":129},{"cath_id":"1.10.287.70","chopping":"314-427","consensus_level":"high","plddt":93.6742,"start":314,"end":427},{"cath_id":"1.20.120","chopping":"143-189_210-310","consensus_level":"high","plddt":84.651,"start":143,"end":310}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P16389","model_url":"https://alphafold.ebi.ac.uk/files/AF-P16389-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P16389-F1-predicted_aligned_error_v6.png","plddt_mean":77.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KCNA2","jax_strain_url":"https://www.jax.org/strain/search?query=KCNA2"},"sequence":{"accession":"P16389","fasta_url":"https://rest.uniprot.org/uniprotkb/P16389.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P16389/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P16389"}},"corpus_meta":[{"pmid":"16002579","id":"PMC_16002579","title":"Voltage 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replicated across brain regions, >300 citations\",\n      \"pmids\": [\"8046438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Kv1.2 shows complex differential subcellular distribution in neurons: concentrated in dendrites of hippocampal/cortical pyramidal and Purkinje cells, but predominantly in nerve terminals of cerebellar basket cells, suggesting Kv1.2-containing channels play diverse functional roles depending on neuronal cell type and subcellular compartment.\",\n      \"method\": \"Combined in situ hybridization and immunocytochemistry in rat brain\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct subcellular localization with functional inference, >150 citations\",\n      \"pmids\": [\"8158277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Kv1.2 homomers are responsible for two-thirds of presynaptic low-threshold K+ current at the calyx of Held, are located in the transition zone between axon and synaptic terminal, and suppress terminal hyperexcitability by limiting depolarizing after-potentials that would otherwise generate additional action potentials.\",\n      \"method\": \"Selective pharmacological blockade (tityustoxin-Kα and DTX-K) combined with current-clamp and paired pre/postsynaptic recordings in rat calyx of Held\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — selective toxin dissection combined with functional electrophysiology, replicated with paired recordings, >130 citations\",\n      \"pmids\": [\"12777451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Receptor protein tyrosine phosphatase alpha (RPTPalpha) co-immunoprecipitates with Kv1.2 in an m1 muscarinic receptor-dependent manner, directly binds N- and C-termini of Kv1.2 in vitro, and overexpression of RPTPalpha reverses tyrosine kinase-induced phosphorylation and suppression of Kv1.2 current, revealing a mechanism whereby GPCR-mediated Kv1.2 suppression depends on coordinate regulation of PTK and PTP activities.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assays, Xenopus oocyte electrophysiology, biochemical phosphorylation analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including reciprocal co-IP, in vitro binding, and functional electrophysiology\",\n      \"pmids\": [\"9878055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The Kv1.2 alpha-subunit mediates O2-sensitive K+ current in PC12 cells; anti-Kv1.2 antibody dialyzed intracellularly completely blocked the O2-sensitive current, and recombinant Kv1.2 expressed in Xenopus oocytes was inhibited by hypoxia, demonstrating Kv1.2 confers O2 sensitivity to this channel.\",\n      \"method\": \"Intracellular antibody blockade in patch clamp, Xenopus oocyte expression, Western blot\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct intracellular antibody blockade plus recombinant expression, multiple orthogonal methods\",\n      \"pmids\": [\"10790158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Kv1.2 associates with the actin-binding protein cortactin; the interaction maps to a 19-amino acid span in the Kv1.2 C-terminus; tyrosine phosphorylation of specific C-terminal tyrosines attenuates cortactin binding; M1 muscarinic receptor activation reduces cortactin-Kv1.2 interaction; and Kv1.2 mutants deficient in cortactin binding exhibit strongly attenuated ionic current, demonstrating a phosphorylation-dependent interaction with the actin cytoskeleton that regulates channel current.\",\n      \"method\": \"Co-immunoprecipitation, purified recombinant protein binding assays, immunocytochemistry, electrophysiology in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted direct binding with purified proteins, mutagenesis, and functional electrophysiology\",\n      \"pmids\": [\"12151401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cortactin directly regulates Kv1.2 endocytosis; pull-down assays confirmed direct Kv1.2-cortactin interaction that is reduced by tyrosine phosphorylation; FRET demonstrated in vivo interaction; cortactin's C-terminal tyrosines, fourth repeat actin-binding domain, and N-terminal Arp2/3-binding region are critical for Kv1.2 regulation, while cortactin's SH3 (dynamin-binding) domain is not required despite dynamin-dependent endocytosis.\",\n      \"method\": \"Recombinant pull-down, FRET, flow cytometry, cortactin gene replacement, site-directed mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including FRET, reconstituted pull-down, and mutagenesis with functional readouts\",\n      \"pmids\": [\"17959782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"C-terminal phosphorylation of Kv1.2 at pS440/pS441 (identified by tandem MS from rat, human, and mouse brain) is present only on post-ER/cell surface Kv1.2, not on newly synthesized ER-localized protein; elimination of these phosphorylation sites reduces cell surface expression and functional Kv1.2 channel expression; S449 phosphorylation regulates phosphorylation at S440/S441 and also affects surface expression.\",\n      \"method\": \"Tandem mass spectrometry phosphoproteomics, site-directed mutagenesis, cell surface biotinylation, electrophysiology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — MS-identified in vivo sites confirmed by mutagenesis and functional trafficking assays across multiple species\",\n      \"pmids\": [\"18056633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Secretin decreases cell-surface Kv1.2 levels in cerebellar slices by modulating Kv1.2 endocytic trafficking via adenylate cyclase/PKA pathway; this effect is mimicked by forskolin and blocked by AC or PKA inhibitors; Kv1.2 endocytosis occurs in basket cell axon terminals and Purkinje cell dendrites; secretin or Kv1.2 inhibition enhances eyeblink conditioning acquisition.\",\n      \"method\": \"Cell-surface protein biotinylation, cerebellar slice pharmacology, behavioral testing (eyeblink conditioning) in rat\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biochemical trafficking assay + pharmacological dissection + behavioral consequence, multiple methods\",\n      \"pmids\": [\"22764231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"cAMP maintains Kv1.2 homeostasis through two distinct pathways: a PKA-dependent pathway that controls steady-state channel turnover (basal PKA inhibition elevates surface Kv1.2), and a PKA-independent pathway (elevated cAMP increases surface Kv1.2 by inhibiting endocytosis).\",\n      \"method\": \"Cell-surface biotinylation, pharmacological inhibitors of PKA and endocytosis, functional expression assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean biochemical and pharmacological dissection in single lab\",\n      \"pmids\": [\"18003609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Kv1.2-containing channels underlie a slowly inactivating, low-threshold K+ current in striatal medium spiny neurons; toxin studies (alpha-DTX sensitive, but not DTX-K, agitoxin-2, or margatoxin) implicated Kv1.2 subunits; blockade of these channels reduced first-spike latency and increased discharge frequency from hyperpolarized membrane potentials, establishing a role in regulating state transitions and repetitive discharge.\",\n      \"method\": \"Pharmacological dissection with Kv1-selective toxins, whole-cell voltage/current clamp in acutely isolated neurons and slices, RT-PCR\",\n      \"journal\": \"Journal of neurophysiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — selective pharmacological dissection with multiple toxins + functional electrophysiology in native cells and slices\",\n      \"pmids\": [\"13679409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cocaine exposure triggers a sigma-1 receptor (Sig-1R)-dependent upregulation of D-type K+ current in nucleus accumbens neurons through a persistent protein-protein association between Sig-1R and Kv1.2 channels, accompanied by redistribution of both proteins from intracellular compartments to the plasma membrane, resulting in neuronal hypoactivity.\",\n      \"method\": \"Co-immunoprecipitation, ex vivo and in vitro electrophysiology, subcellular fractionation/trafficking assays, behavioral studies\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, subcellular redistribution assays, and electrophysiological validation with behavioral consequence, >170 citations\",\n      \"pmids\": [\"23332758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A lncRNA antisense to Kcna2 (Kcna2 antisense RNA) is induced by nerve injury in DRG via activation of myeloid zinc finger protein 1 (MZF1, which binds the antisense RNA gene promoter); this lncRNA silences Kcna2 expression by an antisense mechanism, reduces total voltage-gated K+ current, increases DRG neuron excitability, and produces neuropathic pain symptoms.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), reporter assay, antisense RNA overexpression/knockdown, patch-clamp electrophysiology, behavioral pain testing in rats\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods: ChIP, functional electrophysiology, and behavioral phenotype; highly cited\",\n      \"pmids\": [\"23792947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"De novo KCNA2 mutations cause epileptic encephalopathy through two opposite mechanisms: loss-of-function mutations (dominant-negative current amplitude reduction) produce focal seizures and multifocal epileptiform discharges, while gain-of-function mutations (permanently open channels with hyperpolarizing shift of voltage-dependent activation) produce more severe epilepsy and ataxia, establishing genotype-phenotype correlations.\",\n      \"method\": \"Next-generation sequencing, functional studies in Xenopus oocytes (two-microelectrode voltage clamp), site-directed mutagenesis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional characterization in expression system with electrophysiology and multiple mutations, >200 citations\",\n      \"pmids\": [\"25751627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DNMT3a methylates the Kcna2 promoter region in injured DRG neurons (induced via activation of transcription factor Oct1), silencing Kcna2 expression; blocking DNMT3a prevents promoter methylation, rescues Kcna2 expression and Kv current, reduces neuronal excitability, and attenuates neuropathic pain.\",\n      \"method\": \"ChIP, bisulfite sequencing, reporter assays, DRG microinjection of virus expressing DNMT3a or shRNA, patch-clamp electrophysiology, behavioral pain testing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including ChIP, bisulfite sequencing, electrophysiology, and behavioral phenotyping\",\n      \"pmids\": [\"28270689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"G9a (euchromatic histone-lysine N-methyltransferase 2) contributes to nerve injury-induced downregulation of Kcna2 in DRG; blocking G9a increase rescues Kcna2 mRNA and protein expression; mimicking G9a increase reduces Kcna2, reduces Kv current, increases DRG neuron excitability, and produces neuropathic pain.\",\n      \"method\": \"Western blot, qRT-PCR, intrathecal siRNA injection, patch-clamp electrophysiology, behavioral pain testing in rats\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function and gain-of-function with electrophysiological and behavioral readouts, single lab\",\n      \"pmids\": [\"27874088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DNMT1 acts as a de novo methyltransferase in injured DRG neurons (upregulated via CREB-mediated transcriptional activation of Dnmt1); it methylates the Kcna2 promoter and 5'-UTR, represses Kcna2 expression, increases neuronal excitability, and contributes to neuropathic pain genesis.\",\n      \"method\": \"ChIP, bisulfite sequencing, DRG microinjection of siRNA/AAV, patch-clamp electrophysiology, behavioral pain testing in mice\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, bisulfite sequencing, functional electrophysiology, and behavioral phenotyping with mechanistic pathway defined\",\n      \"pmids\": [\"31182635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"D2 dopamine autoreceptor (D2-AR) activation increases Kv1.2 currents through Gβγ subunit signaling; D2-AR and Kv1.2-containing channels physically associate (co-immunoprecipitation in striatal tissue); Kv1.2-specific blockade or Kv1.2 knockout attenuates D2-AR-mediated inhibition of axonal dopamine overflow, demonstrating Kv1.2 as a downstream effector of D2-AR in nigrostriatal DA release regulation.\",\n      \"method\": \"Fast scan cyclic voltammetry, Kv1.2 knockout mice, selective pharmacological blockade, co-immunoprecipitation, K+ current recordings in co-transfected cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods: KO mice, selective blocker, co-IP, and electrophysiology\",\n      \"pmids\": [\"21233214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PKA phosphorylates Kv1.2 specifically at Ser-449 (confirmed by in vitro phosphorylation, MALDI-TOF MS, MS/MS, and in situ phosphorylation in HEK293 cells); PKA-induced phosphorylation at Ser-449 increases Kv1.2 current amplitude, identified as a molecular mechanism for vasodilatory agonist modulation of Kv1 channels via PKA.\",\n      \"method\": \"In vitro phosphorylation, MALDI-TOF MS/MS, site-directed mutagenesis, whole-cell and inside-out patch clamp electrophysiology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay + MS confirmation + mutagenesis + functional electrophysiology\",\n      \"pmids\": [\"19389710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Glycosylation state of Kv1.2 affects trafficking, gating, and action potentials: preventing N-glycosylation decreases cell surface expression ~40% via increased ER retention (rescued by Kv1.4 but not Kvβ2); increasing glycosylation shifts V(1/2) negatively and increases activation kinetics; decreasing glycosylation has opposite effects consistent with a surface potential mechanism for activation but a conformational mechanism for deactivation.\",\n      \"method\": \"Site-directed mutagenesis to alter glycosylation sites, Western blot, immunocytochemistry, whole-cell patch clamp, computational action potential simulation\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis + trafficking + electrophysiology in single study\",\n      \"pmids\": [\"17324383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"N-linked glycosylation of Kv1.2 is required for forward trafficking to the cell membrane; both wild-type and non-glycosylated Kv1.2 are internalized at comparable rates, but non-glycosylated channels are degraded faster after internalization; removal of sialic acids from cell-surface Kv1.2 also increases degradation of internalized channels.\",\n      \"method\": \"Site-directed mutagenesis, cell surface biotinylation, glycosidase treatment, pulse-chase experiments in COS-7 cells and hippocampal neurons\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis and biochemical trafficking assays with multiple orthogonal approaches\",\n      \"pmids\": [\"27377235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Kv1.2 activation gating is bimodal ('fast' and 'slow' modes); introduction of a positive charge at or around threonine 252 in the S2-S3 linker abolishes 'slow' activation gating; cytoplasm dialysis or patch excision switches gating from slow to fast, implicating cytoplasmic regulators in the gating mode switch.\",\n      \"method\": \"Chimeric channel construction, site-directed mutagenesis, whole-cell and excised patch-clamp electrophysiology in HEK293 cells\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with functional electrophysiology defining gating switch residue\",\n      \"pmids\": [\"17766348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A conditioning train of action potentials at 10 Hz causes long-term potentiation of intrinsic excitability (LTP-IE) in CA3 pyramidal cells mediated by internalization of Kv1.2 channels; LTP-IE was absent in Kv1.2 knockout mice, required intact distal apical dendrites, back-propagating APs, dendritic Ca2+ signaling, and protein tyrosine kinase activation; endocytosis inhibition blocked LTP-IE.\",\n      \"method\": \"Kv1.2 knockout mice, whole-cell patch clamp, endocytosis inhibition, PTK inhibition, dendritic ablation in hippocampal slices\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mice combined with pharmacological dissection and functional electrophysiology with defined mechanism\",\n      \"pmids\": [\"23981714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Kv1.2 mediates MF-induced heterosynaptic LTP of perforant path inputs in CA3 pyramidal cells; Kv1.2 expression is polarized to distal apical dendrites; downregulation of Kv1.2 preferentially enhances distal PP-evoked EPSPs; this enhancement requires activation of dendritic Na+ channels, and its threshold is lowered by Kv1.2 downregulation.\",\n      \"method\": \"Whole-cell patch clamp in hippocampal slices, immunohistochemistry, compartmental simulation, tetrodotoxin pharmacology, Kv1.2 KO/knockdown\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — electrophysiology with KO and pharmacological validation, single lab\",\n      \"pmids\": [\"26047212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Slc7a5 (a neutral amino acid transporter) interacts with Kv1.2 (identified by mass spectrometry of Kv1.2 multi-protein complexes), reduces total Kv1.2 protein, and dramatically hyperpolarizes voltage-dependence of activation by -47 mV; Slc3a2 (binding partner of Slc7a5) attenuates these effects; neurodevelopmental delay-linked Slc7a5 mutations show localization defects and attenuated effects on Kv1.2.\",\n      \"method\": \"Mass spectrometry interactome, co-expression in Xenopus oocytes, two-electrode voltage clamp, site-directed mutagenesis, confocal imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS-identified interaction confirmed by functional expression and mutagenesis with multiple orthogonal methods\",\n      \"pmids\": [\"30356053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Kv1.2 exhibits use-dependent activation during trains of brief depolarizations (enabled by prepulse potentiation); this property is unique to Kv1.2 among Kv1 channels and is conferred even by a single Kv1.2 subunit in heteromeric channel complexes; use-dependent activation is observed in both mammalian cell lines and primary hippocampal neurons.\",\n      \"method\": \"Voltage-clamp electrophysiology in mammalian cells, primary hippocampal neuron cultures, heteromeric channel co-expression\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional electrophysiology in multiple cell types with heteromeric channel validation\",\n      \"pmids\": [\"25716850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Sigma-1 receptor (Sig-1R) interacts with Kv1.2 at baseline to influence bimodal activation gating; ligand activation of Sig-1R modulates Kv1.2 current amplitude; these effects are abolished by auxiliary subunit Kvβ2 (which occludes the Sig-1R interaction site) and by ALS16-linked Sig-1R mutation E102Q.\",\n      \"method\": \"Co-expression in HEK293 cells, whole-cell patch clamp, site-directed mutagenesis, pharmacological Sig-1R ligand activation\",\n      \"journal\": \"Physiological reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional co-expression study with mutagenesis but limited biochemical validation of direct interaction\",\n      \"pmids\": [\"31222975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Kv1.2 and Kv1.5 form heteromultimeric channels in rabbit portal vein myocytes; 4-AP block of native vascular K(DR) shows voltage-dependent characteristics matching Kv1.2 homomers and Kv1.2/Kv1.5 heterotetramers but not Kv1.5 homomers; charybdotoxin insensitivity of native channels distinguishes them from Kv1.2 homotetramers.\",\n      \"method\": \"Patch clamp electrophysiology, tandem-linked subunit expression in mammalian cells, pharmacological characterization\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional characterization of native and recombinant channels with pharmacological dissection\",\n      \"pmids\": [\"11717161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Molecular dynamics simulations of Kv1.2 in lipid membrane show the voltage-sensing domains undergo important lateral fluctuations consistent with their modular nature; S4 arginines R294 and R297 adopt interfacial positions interacting with water and lipid headgroups, while R300 and R303 interact predominantly with water and E226 in S2; the transmembrane potential is focused over the outer half of the membrane in the arginine-rich region of S4.\",\n      \"method\": \"All-atom molecular dynamics simulation with continuum electrostatic computations\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 computational — MD simulation validated against structural data, no direct mutagenesis confirmation\",\n      \"pmids\": [\"17704179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Kv1.2 and the paddle chimera channel (with Kv2.1 voltage sensor paddle transferred to Kv1.2) produced in Pichia yeast are functional in planar lipid bilayers with properties qualitatively similar to Shaker K+ channel; several functional properties of Kv1.2 are distinct from previously reported Kv1.2 in other systems.\",\n      \"method\": \"Planar lipid bilayer electrophysiology, yeast expression system\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution in planar lipid bilayers with electrophysiological characterization\",\n      \"pmids\": [\"18638484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CryoEM structures of Kv1.2 in open (3.2 Å), C-type inactivated (2.5 Å), α-dendrotoxin-blocked (3.2 Å), and Na+-bound (2.9 Å) states reveal: toxin lysine penetrates the selectivity filter disrupting the outermost ion-binding site; in Na+ solution the selectivity filter remains intact with ion density at each binding site rather than collapsing; C-type inactivated W366F in Na+ shows highly variable protein conformation.\",\n      \"method\": \"Single-particle cryoEM structure determination at near-atomic resolution\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — near-atomic resolution cryoEM structures across multiple functional states with direct mechanistic interpretation\",\n      \"pmids\": [\"39945513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Kv1.2 gating charge measured directly is ~10 elementary charges, ~25% less than Shaker; neutralization of R1 in Kv1.2 S4 decreases voltage sensitivity to ~50% of wild-type, whereas subsequent arginines have much smaller effects (contrasting with Shaker), suggesting the voltage-sensing domain aqueous crevice septum in Kv1.2 may be thicker than in Shaker.\",\n      \"method\": \"Two-electrode voltage clamp in Xenopus oocytes, site-directed mutagenesis of S4 arginines, gating current measurement\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — direct gating charge measurement with systematic mutagenesis\",\n      \"pmids\": [\"25779871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MBD1 (methyl-CpG-binding domain protein 1) represses Kcna2 gene expression in DRG neurons by recruiting DNMT3a to the Kcna2 promoter; DRG MBD1 deficiency blunts nerve injury-induced pain hypersensitivity and reduces acute pain responses; DRG overexpression of MBD1 produces pain hypersensitivity and restores acute pain in MBD1-deficient mice.\",\n      \"method\": \"ChIP for MBD1 and DNMT3a at Kcna2 promoter, DRG-specific knockout/overexpression, behavioral pain testing in mice\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-defined molecular mechanism with loss- and gain-of-function behavioral phenotypes\",\n      \"pmids\": [\"30266739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Transcription factor EBF1 directly binds the Kcna2 gene promoter and activates its transcriptional activity in DRG neurons; nerve injury reduces EBF1 binding to the Kcna2 promoter; EBF1 overexpression reverses CCI-induced Kv1.2 downregulation; EBF1 knockdown reduces Kv1.2 expression and produces pain hypersensitivity.\",\n      \"method\": \"ChIP, reporter assay (Kcna2 promoter-luciferase), AAV-mediated DRG overexpression/knockdown, behavioral pain testing in mice\",\n      \"journal\": \"Translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assay define direct transcriptional activation, with in vivo functional validation\",\n      \"pmids\": [\"37607607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Slc7a5-induced suppression of Kv1.2 current and protein expression is attenuated by Kvβ1.2 co-transfection; however, gating effects of Slc7a5 (disinhibition and hyperpolarizing shift in activation) persist alongside Kvβ-mediated inactivation; Slc7a5 modifies Kvβ-induced inactivation including accelerated inactivation, hyperpolarizing shift of steady-state inactivation, and delayed recovery from inactivation.\",\n      \"method\": \"Co-transfection in Xenopus oocytes, two-electrode voltage clamp, Kv1.2/Kvβ/Slc7a5 triple co-expression\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic electrophysiological dissection of three-way regulatory interaction\",\n      \"pmids\": [\"32311044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Kv1.2 knockout mice have significantly less NREM sleep (-23%) and more waking (+21%) than wild-type littermates at P17, with increased number of waking episodes but no change in REM sleep, establishing that Kv1.2 regulates NREM sleep in mammals.\",\n      \"method\": \"EEG/EMG continuous recording, video monitoring, sleep scoring in Kcna2 knockout mice\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genetic knockout with defined EEG/behavioral phenotype\",\n      \"pmids\": [\"17925011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Kv1.2 is expressed in microglia; blockade of Kv1.2 with tityustoxin-Kα partially recovers intracellular K+ concentration and reduces IL-1β and TNF-α mRNA/protein expression and intracellular ROS production in hypoxia/LPS/ATP-treated microglia, suggesting Kv1.2 regulates microglial proinflammatory cytokine production by modulating intracellular K+ concentration.\",\n      \"method\": \"Pharmacological blockade, quantitative RT-PCR, Western blot, immunofluorescence, intracellular K+ measurement in rat brain and primary microglia\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological loss-of-function with molecular readouts, single lab\",\n      \"pmids\": [\"18627436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Kv1.2 is resistant to acidic pH while Kv1.5 shows enhanced C-type inactivation at acidic pH; a histidine residue in the third extracellular loop of Kv1.5 (H452) accounts for this difference; mutation of H452 to glutamine in Kv1.5 abolishes pH-dependent inactivation, revealing H452 as a pH sensor for C-type inactivation.\",\n      \"method\": \"Two-electrode voltage clamp and cell-attached patch clamp in Xenopus oocytes, site-directed mutagenesis\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis identifies molecular determinant of pH sensitivity with functional validation; relevant to Kv1.2 as the resistant channel\",\n      \"pmids\": [\"10220559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BCAA deficiency activates LAT1 (L-type amino acid transporter 1, i.e. Slc7a5) expression through ATF4, and upregulated LAT1 reduces Kv1.2 localization to the cell membrane, inhibiting Kv1.2 channels and increasing DRG neuronal excitability to cause neuropathic pain in diabetic models.\",\n      \"method\": \"RNA sequencing, label-free quantitative proteomics, western blot, patch-clamp electrophysiology, pharmacological LAT1 inhibition in mouse DRG and HFD/STZ and db/db mouse models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-omics plus electrophysiology plus pharmacological validation in multiple in vivo models\",\n      \"pmids\": [\"38946582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HDAC2, but not HDAC1, regulates Kv1.2 expression in DRG neurons; Kv1.2 co-localizes with HDAC2 in NF200-positive large neurons; HDAC2 siRNA relieves mechanical/thermal hypersensitivity in CCI rats and upregulates Kv1.2, whereas HDAC1 siRNA has no effect on Kv1.2; HDAC2 siRNA in PC12 cells also upregulates Kv1.2.\",\n      \"method\": \"Double-label immunofluorescence, intrathecal siRNA injection, HDAC inhibitor treatment, western blot, qRT-PCR in CCI rats\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — siRNA knockdown with molecular and behavioral readouts but no direct chromatin/promoter assay for HDAC2 at Kcna2\",\n      \"pmids\": [\"31022463\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Kv1.2 is a voltage-gated potassium channel whose crystal and cryoEM structures reveal independent voltage-sensing domains that transduce membrane voltage through S4-S5 linker helices to gate the pore; it is regulated by a complex array of post-translational modifications (tyrosine phosphorylation by PTKs reversed by RPTPα, PKA-mediated phosphorylation at Ser-449/Ser-440/Ser-441, N-glycosylation) that control its trafficking to and from the plasma membrane, and by protein interactions (with cortactin, Sig-1R, Kvβ subunits, and Slc7a5) that modulate its gating and surface expression; epigenetic silencing of Kcna2 (via DNMT3a, DNMT1, G9a, MBD1, and a natural antisense lncRNA) in primary sensory neurons after nerve injury reduces Kv1.2-mediated K+ current, increases neuronal excitability, and drives neuropathic pain, while presynaptically, Kv1.2 suppresses terminal hyperexcitability and mediates D2 autoreceptor regulation of dopamine release.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KCNA2 encodes Kv1.2, a voltage-gated potassium channel that functions as a central regulator of neuronal excitability across diverse brain circuits, controlling presynaptic terminal firing fidelity, dendritic integration, intrinsic plasticity, dopaminergic neurotransmission, and sleep architecture. Structural studies reveal that independent voltage-sensing domains transduce membrane potential changes through S4–S5 linker helices to gate the pore, with gating charge contributed predominantly by the outermost S4 arginine and a unique bimodal (fast/slow) activation property conferred by residues in the S2–S3 linker [PMID:16002579, PMID:17766348, PMID:39945513]. Channel surface expression is dynamically regulated by a convergent set of post-translational mechanisms—tyrosine phosphorylation (modulated by RPTPα and cortactin interaction with the cytoskeleton), PKA phosphorylation at Ser-449/Ser-440/Ser-441, N-glycosylation-dependent ER export, and interactions with Slc7a5 and sigma-1 receptor—that collectively tune Kv1.2-mediated K⁺ current amplitude through endocytic trafficking and gating modulation [PMID:9878055, PMID:12151401, PMID:18056633, PMID:19389710, PMID:30356053, PMID:23332758]. De novo KCNA2 mutations cause epileptic encephalopathy through either loss-of-function (dominant-negative current reduction) or gain-of-function (constitutively open channels) mechanisms [PMID:25751627], and nerve injury–induced epigenetic silencing of Kcna2 by DNMT3a, DNMT1, G9a, MBD1, and a natural antisense lncRNA in dorsal root ganglion neurons reduces Kv1.2 current, increases excitability, and drives neuropathic pain [PMID:23792947, PMID:28270689, PMID:31182635].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing where Kv1.2 protein resides in the nervous system was prerequisite to understanding its functional roles; immunolocalization revealed differential subcellular targeting—synaptic terminals, juxta-paranodes, dendrites—varying by neuronal type, implying participation in distinct heteromultimeric complexes at each site.\",\n      \"evidence\": \"Immunocytochemistry and subcellular fractionation across mouse and rat brain regions\",\n      \"pmids\": [\"8046438\", \"8158277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of heteromultimeric partners at each subcellular site was not determined\", \"Mechanism directing polarized trafficking to specific compartments was unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"The question of how GPCR signaling suppresses Kv1.2 was answered by showing that RPTPα directly binds Kv1.2, counteracts tyrosine-kinase-mediated phosphorylation and current suppression, and is recruited to Kv1.2 in an m1 muscarinic receptor–dependent manner, establishing a phosphorylation-based regulatory axis.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro binding, Xenopus oocyte electrophysiology\",\n      \"pmids\": [\"9878055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the tyrosine kinase phosphorylating Kv1.2 in this pathway was not established\", \"Specific phosphorylated tyrosine residues on Kv1.2 were not mapped\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Discovery that cortactin physically links Kv1.2 to the actin cytoskeleton—and that tyrosine phosphorylation disrupts this interaction—resolved how cytoskeletal association controls channel current magnitude and laid the groundwork for understanding phosphorylation-triggered endocytosis.\",\n      \"evidence\": \"Purified recombinant binding assays, co-immunoprecipitation, mutagenesis, electrophysiology in HEK293 cells; later confirmed by FRET, cortactin domain mutagenesis, and endocytosis assays\",\n      \"pmids\": [\"12151401\", \"17959782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the cortactin–Kv1.2 interface was not determined\", \"Role of Arp2/3-mediated actin remodeling versus simple anchoring in endocytosis was not fully separated\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Selective toxin dissection at the calyx of Held and in striatal neurons demonstrated that Kv1.2 homomers carry the majority of low-threshold presynaptic K⁺ current and suppress terminal hyperexcitability, establishing a specific physiological function for Kv1.2 at defined synapses.\",\n      \"evidence\": \"Tityustoxin-Kα and DTX-K pharmacology combined with paired pre/postsynaptic recordings (calyx) and whole-cell recordings (striatal neurons)\",\n      \"pmids\": [\"12777451\", \"13679409\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of heteromeric Kv1.2-containing channels versus homomers at these synapses was only partially resolved\", \"Mechanisms regulating Kv1.2 density at the presynaptic transition zone were unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The 2.9 Å crystal structure of Kv1.2 resolved a long-standing debate about voltage-sensor topology by showing voltage-sensing domains as modular peripheral units connected to the pore through S4–S5 linker helices, with conserved S4 arginines positioned at the protein–lipid interface.\",\n      \"evidence\": \"X-ray crystallography of full-length Kv1.2\",\n      \"pmids\": [\"16002579\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Only the open-state structure was captured; closed- and inactivated-state conformations were unknown\", \"Lipid interactions were modeled but not directly resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"A cluster of discoveries defined how post-translational modifications control Kv1.2 trafficking: C-terminal phosphorylation at S440/S441 (identified by MS across three species) marks post-ER channels for surface delivery; N-glycosylation promotes ER exit and modulates gating; PKA and cAMP pathways bidirectionally regulate surface expression through endocytosis and turnover.\",\n      \"evidence\": \"Tandem MS phosphoproteomics, site-directed mutagenesis, cell-surface biotinylation, glycosylation-site mutagenesis, pharmacological dissection of cAMP/PKA pathways\",\n      \"pmids\": [\"18056633\", \"17324383\", \"18003609\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The kinase responsible for S440/S441 phosphorylation was not identified\", \"How glycosylation and phosphorylation signals are coordinated was not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of bimodal (fast/slow) activation gating unique to Kv1.2 and mapping of the gating-mode switch to a charge at T252 in the S2–S3 linker revealed an intrinsic regulatory mechanism modifiable by cytoplasmic factors, distinguishing Kv1.2 from other Kv1 channels.\",\n      \"evidence\": \"Chimeric channel construction, site-directed mutagenesis, excised-patch electrophysiology in HEK293 cells\",\n      \"pmids\": [\"17766348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The identity of the endogenous cytoplasmic regulator switching gating mode was not determined\", \"Structural basis of the two gating conformations was not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"PKA phosphorylation of Kv1.2 was mapped to Ser-449 by mass spectrometry and mutagenesis, with functional electrophysiology showing this modification increases current amplitude, providing a molecular mechanism for vasodilatory agonist modulation of Kv1 channels.\",\n      \"evidence\": \"In vitro kinase assay, MALDI-TOF MS/MS, site-directed mutagenesis, whole-cell and inside-out patch clamp\",\n      \"pmids\": [\"19389710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether S449 phosphorylation operates in vascular smooth muscle in vivo was not confirmed\", \"Cross-talk between S449 and the S440/S441 phosphorylation cluster was only partially explored\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"D2 dopamine autoreceptor activation was shown to increase Kv1.2 current via Gβγ signaling, with physical association between D2-AR and Kv1.2 in striatum; Kv1.2 KO attenuated D2-AR-mediated inhibition of dopamine overflow, establishing Kv1.2 as a downstream effector of presynaptic dopamine autoreceptor signaling.\",\n      \"evidence\": \"Fast-scan cyclic voltammetry in Kv1.2 KO mice, co-immunoprecipitation from striatal tissue, selective pharmacological blockade\",\n      \"pmids\": [\"21233214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Gβγ directly binds Kv1.2 or acts through an intermediary was not resolved\", \"Contribution of heteromeric Kv1.2 complexes versus homomers in dopamine terminals was not dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two parallel discoveries connected Kv1.2 downregulation to neuropathic pain and synaptic plasticity: a nerve injury–induced antisense lncRNA (driven by MZF1) silences Kcna2 in DRG to increase excitability and produce pain; activity-dependent Kv1.2 endocytosis in CA3 dendrites mediates long-term potentiation of intrinsic excitability.\",\n      \"evidence\": \"ChIP, antisense RNA overexpression/knockdown, patch-clamp and behavioral pain testing (neuropathic pain); Kv1.2 KO mice, endocytosis inhibition, PTK blockade in hippocampal slices (LTP-IE)\",\n      \"pmids\": [\"23792947\", \"23981714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which the antisense lncRNA degrades or silences Kcna2 mRNA at a molecular level was not fully elucidated\", \"Whether LTP-IE-associated Kv1.2 endocytosis uses the same cortactin/tyrosine-phosphorylation pathway was not confirmed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Sigma-1 receptor was found to form a persistent protein complex with Kv1.2, promoting its redistribution to the plasma membrane and upregulating D-type K⁺ current in nucleus accumbens after cocaine exposure, establishing a Sig-1R–Kv1.2 axis in addiction-related neuronal hypoactivity.\",\n      \"evidence\": \"Co-immunoprecipitation, subcellular fractionation, ex vivo electrophysiology, behavioral studies in cocaine-exposed rats\",\n      \"pmids\": [\"23332758\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The Sig-1R binding site on Kv1.2 was not mapped\", \"Whether Kvβ subunits occlude Sig-1R interaction in vivo (as later suggested in heterologous cells) was not tested in native tissue\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"De novo KCNA2 mutations were shown to cause epileptic encephalopathy through two mechanistically opposite routes—loss-of-function (dominant-negative) and gain-of-function (constitutively open)—with distinct clinical presentations, establishing genotype-phenotype correlations for KCNA2 channelopathy.\",\n      \"evidence\": \"Next-generation sequencing of patient cohorts, Xenopus oocyte voltage-clamp functional characterization\",\n      \"pmids\": [\"25751627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neuron-type-specific consequences of each mutation class were not characterized\", \"Whether gain-of-function mutations alter Kv1.2 heteromultimerization was not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The epigenetic silencing pathway was extended: DNMT3a (recruited by Oct1 and MBD1) and later DNMT1 (activated by CREB) were shown to directly methylate the Kcna2 promoter in injured DRG neurons, suppressing Kv1.2 and driving neuropathic pain; G9a and HDAC2 also contribute to injury-induced Kcna2 repression.\",\n      \"evidence\": \"ChIP, bisulfite sequencing, reporter assays, viral overexpression/knockdown, siRNA, electrophysiology, behavioral pain testing in rodent models\",\n      \"pmids\": [\"28270689\", \"31182635\", \"27874088\", \"31022463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchical ordering of DNMT3a, DNMT1, G9a, and HDAC2 contributions was not determined\", \"Whether these epigenetic modifications are reversible after nerve regeneration was not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Slc7a5 (LAT1) was identified as a novel Kv1.2 interactor that dramatically hyperpolarizes voltage-dependent activation by ~47 mV and reduces total protein levels, with Kvβ and Slc3a2 providing counterbalancing modulation; this interaction has pathophysiological relevance in diabetic neuropathic pain where BCAA deficiency upregulates LAT1.\",\n      \"evidence\": \"Mass spectrometry interactome, co-expression electrophysiology, mutagenesis in Xenopus oocytes; RNA-seq, proteomics, and pharmacological LAT1 inhibition in DRG and diabetic mouse models\",\n      \"pmids\": [\"30356053\", \"32311044\", \"38946582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the Slc7a5–Kv1.2 interaction is unknown\", \"Stoichiometry of Slc7a5 modulation of native neuronal Kv1.2 complexes is uncharacterized\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"CryoEM structures in open, C-type inactivated, toxin-blocked, and Na⁺-bound states resolved how α-dendrotoxin blocks by inserting a lysine into the outermost selectivity filter site and showed the selectivity filter remains structurally intact in Na⁺ rather than collapsing, revising models of ion selectivity and C-type inactivation.\",\n      \"evidence\": \"Single-particle cryoEM at 2.5–3.2 Å resolution across four functional states\",\n      \"pmids\": [\"39945513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Resting/closed-state structure has not been captured\", \"Lipid-dependent modulation of the selectivity filter in native membranes was not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of bimodal gating and its endogenous cytoplasmic regulator, the resting-state conformation of the voltage sensor, the hierarchical organization of multiple epigenetic silencing pathways converging on Kcna2, and how heteromultimeric assembly with other Kv1 subunits determines subcellular targeting and functional diversity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No resting-state Kv1.2 structure exists\", \"Identity of the cytoplasmic factor switching bimodal gating is unknown\", \"Whether therapeutic reversal of Kcna2 epigenetic silencing can treat neuropathic pain is untested in humans\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 3, 5, 11, 14, 31]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 8, 12, 21]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [8, 20]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 2, 3, 11, 13, 14, 18, 23, 24]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 9, 12, 18, 19]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 3, 5, 14, 31]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [7, 8, 9, 20, 21]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PTPRA\",\n      \"CTTN\",\n      \"SIGMAR1\",\n      \"SLC7A5\",\n      \"DRD2\",\n      \"MBD1\",\n      \"DNMT3A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}