{"gene":"KCNA2","run_date":"2026-06-10T01:55:23","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 they perform mechanical work on the pore through the 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 are on a lipid-facing surface while two are buried in the voltage sensor.","method":"X-ray crystallography","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structure of the mammalian channel, foundational structural study widely replicated and cited","pmids":["16002579"],"is_preprint":false},{"year":1994,"finding":"Kv1.2 protein is localized to multiple subcellular compartments in mouse brain neurons including cell somata, juxta-paranodal regions of myelinated axons, synaptic terminals, unmyelinated axons, and proximal dendrites, with a differential pattern from Kv1.1 that depends on cell type.","method":"Immunocytochemistry / subcellular fractionation in mouse brain","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct immunolocalization with multiple neuronal compartments characterized; independently confirmed by multiple labs","pmids":["8046438"],"is_preprint":false},{"year":1994,"finding":"In rat brain, Kv1.2 shows complex differential subcellular distribution: concentrated in dendrites of hippocampal/cortical pyramidal cells and Purkinje cells, but predominantly in nerve terminals of cerebellar basket cells. The authors hypothesize this arises from association with different heterologous subunits in different cell types.","method":"Combined in situ hybridization and immunocytochemistry in rat brain","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct immunolocalization with cell-type resolution; independently replicated across multiple labs","pmids":["8158277"],"is_preprint":false},{"year":1999,"finding":"Receptor protein tyrosine phosphatase alpha (RPTPalpha) co-immunoprecipitates with Kv1.2 in an m1 muscarinic acetylcholine receptor (mAChR)-dependent manner; N- and C-termini of Kv1.2 bind RPTPalpha in vitro; overexpression of RPTPalpha increases resting Kv1.2 current and reverses tyrosine kinase-induced phosphorylation and suppression of Kv1.2 current, establishing RPTPalpha as a phosphatase that opposes GPCR-mediated channel suppression.","method":"Co-immunoprecipitation, in vitro binding assay, Xenopus oocyte electrophysiology, biochemical phosphorylation analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP plus in vitro binding plus functional electrophysiology in multiple systems","pmids":["9878055"],"is_preprint":false},{"year":2002,"finding":"Kv1.2 associates with the actin-binding protein cortactin; this interaction is direct (shown with purified recombinant proteins), requires a 19-amino acid span in the Kv1.2 C-terminus, and is attenuated by tyrosine phosphorylation of specific C-terminal tyrosines. M1 muscarinic receptor activation reduces cortactin-Kv1.2 interaction, and mutant Kv1.2 channels deficient in cortactin binding exhibit strongly attenuated ionic 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 / Strong — direct binding with purified proteins plus functional validation, reciprocal co-IP, site-directed mutagenesis","pmids":["12151401"],"is_preprint":false},{"year":2007,"finding":"Cortactin is required for Kv1.2 regulation: pull-down assays confirmed direct interaction reduced by tyrosine phosphorylation of Kv1.2; FRET demonstrated in vivo interaction; cortactin's fourth repeat actin-binding domain and N-terminal Arp2/3-binding region (but not the dynamin-binding SH3 domain) are critical for Kv1.2 endocytosis; manipulating the cortactin-binding site within Kv1.2 confirms cortactin proximity influences channel function.","method":"Pull-down with recombinant proteins, FRET, flow cytometry, cortactin gene replacement, endocytosis assays","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including FRET, pull-down, mutagenesis, functional assay","pmids":["17959782"],"is_preprint":false},{"year":2007,"finding":"A cluster of cytoplasmic C-terminal phosphorylation sites (pS434, pS440, pS441, pS449) on Kv1.2 regulates its trafficking. Phosphorylation at pS440/pS441 is present only on post-ER/cell-surface Kv1.2, not on newly synthesized ER-localized channel; elimination of these sites by mutation reduces cell-surface expression and functional expression. pS449 phosphorylation regulates pS440/pS441 phosphorylation. These mutations also suppress trafficking of Kv1.2/Kv1.4 heteromeric channels.","method":"Tandem MS of Kv1.2 purified from rat/human/mouse brain, site-directed mutagenesis, cell-surface expression assays","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo phosphosite identification by MS from multiple species combined with mutagenesis and functional validation","pmids":["18056633"],"is_preprint":false},{"year":2003,"finding":"In the calyx of Held presynaptic terminal, Kv1.2 homomers are responsible for two-thirds of the presynaptic low-threshold K+ current, while Kv1.1/Kv1.2 heteromers contribute the remaining current. Kv1.2 channels are located in the transition zone between the axon and synaptic terminal. Blocking Kv1.2 (with TsTX-Kα) increases the depolarizing after-potential amplitude following each action potential, bringing the terminal closer to threshold and evoking additional EPSCs in postsynaptic cells, establishing Kv1.2 as a suppressor of presynaptic terminal hyperexcitability.","method":"Selective toxin pharmacology (TsTX-Kα, DTX-K), current-clamp and voltage-clamp recordings from calyx of Held, paired pre/postsynaptic recordings","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — selective pharmacology with multiple toxins, direct pre/postsynaptic paired recordings, defined functional readout","pmids":["12777451"],"is_preprint":false},{"year":2000,"finding":"The Kv1.2 α-subunit comprises the O2-sensitive K+ channel in PC12 cells: intracellularly dialyzed anti-Kv1.2 antibody completely blocked the O2-sensitive K+ current, whereas anti-Kv2.1 antibody had no effect; recombinant Kv1.2 expressed in Xenopus oocytes was inhibited by hypoxia, while Kv2.1 was not, establishing Kv1.2 as the molecular substrate of the hypoxic K+ current.","method":"Intracellular antibody dialysis, Xenopus oocyte expression, Western blot, whole-cell voltage clamp","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — intracellular antibody occlusion plus recombinant expression, two independent functional approaches","pmids":["10790158"],"is_preprint":false},{"year":2007,"finding":"N-glycosylation state of Kv1.2 affects its gating (V1/2 shifts, activation/deactivation kinetics, C-type inactivation) via a surface potential mechanism, and preventing N-glycosylation decreases cell-surface Kv1.2 expression by ~40% primarily through partial ER retention; this trafficking defect is rescued by co-expression with glycosylated Kv1.4 but not Kvβ2.","method":"Site-directed mutagenesis, whole-cell patch clamp, glycosidase treatment, confocal imaging, western blot","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus functional electrophysiology plus trafficking assays, single lab","pmids":["17324383"],"is_preprint":false},{"year":2007,"finding":"cAMP regulates Kv1.2 surface levels through two opposing trafficking pathways: a PKA-dependent pathway controlling steady-state channel turnover (basal PKA activity promotes endocytosis), and a PKA-independent pathway that elevates surface Kv1.2 by inhibiting endocytosis when cAMP is elevated above basal.","method":"Surface biotinylation, pharmacological inhibitors of PKA, endocytosis inhibitors, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — surface expression assays with multiple pharmacological tools, single lab","pmids":["18003609"],"is_preprint":false},{"year":2009,"finding":"PKA phosphorylates Kv1.2 specifically at Ser-449 in the C-terminus; in vitro and in situ phosphorylation at this site were confirmed by MS; PKA-induced increase in Kv1.2 current amplitude is abolished by the S449A mutation, establishing Ser-449 as the functionally critical PKA phosphorylation site for channel regulation.","method":"In vitro phosphorylation, MALDI-TOF MS, MS/MS, site-directed mutagenesis, whole-cell and inside-out patch clamp","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical phosphosite identification by MS combined with mutagenesis and functional electrophysiology in multiple configurations","pmids":["19389710"],"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, caused by persistent protein-protein association between Sig-1Rs and Kv1.2 channels, associated with redistribution of both proteins from intracellular compartments to the plasma membrane.","method":"Co-immunoprecipitation in striatal tissue, ex vivo and in vitro electrophysiology, subcellular fractionation, behavioral cocaine response assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP in native tissue plus electrophysiology plus localization, multiple orthogonal methods","pmids":["23332758"],"is_preprint":false},{"year":2011,"finding":"Kv1.2 contributes to D2 dopamine autoreceptor (D2-AR) regulation of axonal dopamine overflow: selective Kv1.2 blockade and Kv1.2 knockout both attenuate D2-AR-mediated inhibition of DA overflow; D2-AR activation increases Kv1.2 currents in co-transfected cells via Gβγ subunit signaling; D2-AR and Kv1.2 physically associate in striatal tissue by immunoprecipitation.","method":"Fast-scan cyclic voltammetry in striatal slices, Kv1.2 KO mice, selective toxin blockade, electrophysiology, immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus pharmacology plus co-IP in native tissue plus functional electrophysiology","pmids":["21233214"],"is_preprint":false},{"year":2013,"finding":"Activity-dependent downregulation of Kv1.2 in hippocampal CA3 pyramidal cells underlies long-term potentiation of intrinsic excitability (LTP-IE): a conditioning train of 20 APs at 10 Hz causes persistent reduction in D-type K+ current; LTP-IE is abolished by inhibition of endocytosis or protein tyrosine kinase, and is absent in Kv1.2 knockout mice, indicating it is mediated by internalization of Kv1.2 from distal apical dendrites triggered by back-propagating AP-induced dendritic Ca2+ signaling.","method":"Whole-cell patch clamp, endocytosis inhibitors, PTK inhibitors, Kv1.2 KO mice, dendritic Ca2+ imaging","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO controls plus pharmacology plus electrophysiology with defined cellular mechanism","pmids":["23981714"],"is_preprint":false},{"year":2012,"finding":"Secretin decreases cell-surface Kv1.2 levels in rat cerebellar slices by modulating Kv1.2 endocytic trafficking; this effect is mimicked by adenylate cyclase activation (forskolin) and blocked by pharmacological inhibitors of AC or PKA, localizing the effect to basket cell axon terminals and Purkinje cell dendrites. Intra-cerebellar infusion of a Kv1.2 inhibitor or secretin both enhance acquisition of eyeblink conditioning.","method":"Cell-surface protein biotinylation, pharmacological inhibitors, cerebellar slice imaging, behavioral eyeblink conditioning","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biotinylation trafficking assay plus behavioral readout, single lab","pmids":["22764231"],"is_preprint":false},{"year":2015,"finding":"De novo mutations in KCNA2 cause epileptic encephalopathy through two distinct mechanisms: dominant-negative loss-of-function (almost complete current reduction) causing multifocal epileptiform discharges and focal seizures, or gain-of-function (permanently open channels with drastic negative shift in activation) causing a more severe encephalopathy with generalized seizures, as established by functional electrophysiology of the mutant channels.","method":"Xenopus oocyte two-electrode voltage clamp, next-generation sequencing, functional expression of mutant channels","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct functional characterization of multiple mutants in heterologous expression system with clear genotype-phenotype correlation replicated in follow-up cohort studies","pmids":["25751627"],"is_preprint":false},{"year":2017,"finding":"DNA methyltransferase DNMT3a represses Kcna2 expression by methylating the Kcna2 promoter region in DRG neurons after nerve injury; blocking DNMT3a prevents nerve injury-induced methylation of the Kcna2 promoter, rescues Kcna2 expression and Kv current, and attenuates neuropathic pain. Mimicking DNMT3a upregulation reduces Kcna2 promoter activity, Kcna2 expression, and Kv current and causes neuropathic pain symptoms.","method":"Chromatin methylation assay, luciferase reporter assay, siRNA knockdown, AAV overexpression, patch clamp, behavioral pain assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional manipulation (KD and OE) with molecular mechanism (promoter methylation), functional electrophysiology, and behavioral readout","pmids":["28270689"],"is_preprint":false},{"year":2016,"finding":"G9a (euchromatic histone-lysine N-methyltransferase 2) epigenetically silences Kcna2 in injured DRG neurons: blocking nerve injury-induced G9a increase rescues Kcna2 mRNA and protein expression; mimicking the increase decreases Kcna2 expression, reduces Kv current, and increases DRG neuronal excitability. G9a mRNA is co-localized with Kcna2 mRNA in DRG neurons.","method":"siRNA, AAV-mediated overexpression, western blot, qPCR, patch clamp, immunofluorescence","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation with functional electrophysiology, single lab","pmids":["27874088"],"is_preprint":false},{"year":2019,"finding":"DNMT1, acting as a de novo methyltransferase, represses Kcna2 expression by increasing DNA methylation within the promoter and 5'-UTR of the Kcna2 gene in injured DRG, downstream of CREB-mediated Dnmt1 transcriptional activation; blocking DNMT1 upregulation prevents Kcna2 methylation, rescues Kv current and reduces DRG neuronal hyperexcitability.","method":"CREB knockout/overexpression, DNMT1 siRNA, bisulfite sequencing of Kcna2 promoter, patch clamp, behavioral assays","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter methylation analysis plus functional electrophysiology, single lab","pmids":["31182635"],"is_preprint":false},{"year":2007,"finding":"Kv1.2 channels exhibit two distinct activation gating modes ('fast' and 'slow') switchable by a prepulse; the S2-S3 linker threonine residue (T252) acts as a switch between these modes — introduction of a positive charge at this position abolishes 'slow' activation gating; cytoplasm dialysis or patch excision also switches gating from slow to fast, implicating cytoplasmic regulators.","method":"Whole-cell and inside-out patch clamp, chimera construction between Kv1.2 and Kv1.5, point mutagenesis, cytoplasm dialysis","journal":"Biophysical journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis plus chimera analysis plus multiple electrophysiology configurations in single rigorous study","pmids":["17766348"],"is_preprint":false},{"year":2001,"finding":"The dominant form of vascular delayed rectifier K+ channel in rabbit portal vein myocytes involves heteromultimeric association of Kv1.2 and Kv1.5 subunits: native K(DR) properties including 4-AP-induced positive shift in voltage dependence of activation are reproduced by Kv1.5/Kv1.2 heteromers or tandem constructs but not by Kv1.5 homotetramers alone; native K(DR) was insensitive to charybdotoxin (which blocks Kv1.2 homomers), consistent with heteromeric composition.","method":"Patch clamp, expression of heteromeric and tandem-linked channel constructs in mammalian cells, pharmacological profiling","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional comparison of native vs recombinant heteromeric channels, single lab","pmids":["11717161"],"is_preprint":false},{"year":2018,"finding":"Slc7a5, a neutral amino acid transporter, forms a multi-protein complex with Kv1.2 (identified by mass spectrometry), dramatically hyperpolarizes Kv1.2 voltage-dependence of activation by -47 mV, reduces total Kv1.2 protein, and accelerates inactivation causing channels to accumulate in a non-conducting state. Slc3a2 (a known Slc7a5 binding partner) attenuates these effects. Epilepsy-linked gain-of-function Kv1.2 mutants show enhanced sensitivity to Slc7a5.","method":"Mass spectrometry interactome screen followed by patch clamp, western blot, co-expression with wild-type and disease mutant channels","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS identification plus functional electrophysiology with multiple mutants, mechanistic pathway placement, single lab with multiple orthogonal methods","pmids":["30356053"],"is_preprint":false},{"year":2020,"finding":"Slc7a5 regulates Kv1.2 in the presence of Kvβ1.2: Slc7a5-induced suppression of Kv1.2 current and protein is attenuated by Kvβ1.2 co-expression, but gating effects of Slc7a5 (disinhibition, hyperpolarizing shift) persist alongside Kvβ-mediated inactivation. Slc7a5 also accelerates Kvβ-induced inactivation, shifts steady-state inactivation, and delays recovery, indicating convergent regulation by both accessory proteins.","method":"Whole-cell patch clamp, western blot, co-transfection in HEK cells","journal":"The Journal of general physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional electrophysiology with multiple subunit combinations, single lab","pmids":["32311044"],"is_preprint":false},{"year":2015,"finding":"Kv1.2 exhibits unique use-dependent activation during trains of brief depolarizations (arising from prepulse potentiation); this property is not shared by other Kv1 subtypes but is conferred in heteromeric channel complexes containing even a single Kv1.2 subunit; use-dependent activation is observed in mammalian cell lines and primary hippocampal neurons.","method":"Whole-cell patch clamp in HEK cells and primary hippocampal neuron cultures, heteromeric channel co-expression","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology in multiple cell systems with defined subunit composition, single lab","pmids":["25716850"],"is_preprint":false},{"year":2017,"finding":"Extracellular redox environment regulates Kv1.2 gating mode: reducing agents promote a shift to an 'inhibited' gating mode that resists opening and causes pronounced use-dependent activation; this redox sensitivity is absent in other Kv1 channels but is apparent in heteromeric channels containing Kv1.2 subunits; mutagenesis of candidate cysteines fails to abolish redox sensitivity, suggesting an extrinsic redox-sensitive binding partner.","method":"Whole-cell patch clamp, reducing agent application, site-directed mutagenesis of cysteine residues, heteromeric channel expression","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological manipulation plus mutagenesis plus heteromeric channels, single lab; mechanism of redox sensing remains partially unresolved","pmids":["28831076"],"is_preprint":false},{"year":2003,"finding":"Kv1.2-containing channels in striatal medium spiny neurons activate rapidly near resting potential (~-60 mV), inactivate slowly, and account for ~50% of subthreshold K+ current; pharmacological blockade (by tityustoxin-Kα but not by toxins lacking high Kv1.2 affinity) reduces first-spike latency and increases discharge frequency from hyperpolarized membrane potentials, establishing Kv1.2 as a regulator of state transitions in these neurons.","method":"Whole-cell patch clamp, selective toxin pharmacology, current-clamp in acute slices, RT-PCR","journal":"Journal of neurophysiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — selective toxin profiling with multiple blockers plus functional current-clamp recordings in acute slices","pmids":["13679409"],"is_preprint":false},{"year":2013,"finding":"The lncRNA Kcna2 antisense RNA silences Kcna2 expression in DRG primary afferent neurons; its increase after peripheral nerve injury (via activation of transcription factor MZF1 binding to the antisense RNA gene promoter) downregulates Kcna2 mRNA and protein, reduces total voltage-gated K+ current, increases DRG neuron excitability, and produces neuropathic pain. Blocking the antisense RNA increase reverses these effects.","method":"Promoter binding assay (ChIP/EMSA for MZF1), siRNA/overexpression, patch clamp, behavioral pain assays","journal":"Nature neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway from lncRNA to Kcna2 expression to K+ current to behavior; note this is about Kcna2 regulation, not the protein mechanism per se; single lab","pmids":["23792947"],"is_preprint":false},{"year":2015,"finding":"Kv1.2 gating charge is ~10 elementary charges, approximately 25% less than Shaker; neutralization of R1 in the S4 segment decreases voltage sensitivity to ~50% of wild-type, while subsequent arginines have much smaller effects — in contrast to Shaker where the first four basic residues contribute roughly equally, suggesting the VSD septum separating aqueous crevices in Kv1.2 may be thicker than in Shaker.","method":"Two-electrode voltage clamp in Xenopus oocytes, gating current measurements, S4 arginine neutralization mutagenesis","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct gating charge measurement combined with systematic mutagenesis of S4 residues","pmids":["25779871"],"is_preprint":false},{"year":2016,"finding":"N-linked glycosylation of Kv1.2 at the conserved S1-S2 linker site facilitates forward trafficking to the cell membrane and enhances stability of internalized channels by reducing their degradation rate; removal of sialic acids from surface Kv1.2 accelerates degradation of internalized channels.","method":"Glycosidase treatment, N-glycosylation mutants, surface biotinylation, protein half-life assays in COS-7 cells and hippocampal neurons","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus glycosidase treatment plus trafficking assays, single lab","pmids":["27377235"],"is_preprint":false},{"year":2025,"finding":"CryoEM structures of Kv1.2 at near-atomic resolution 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: (1) dendrotoxin lysine penetrates into the selectivity filter coordinated by carbonyls, displacing the outermost ion-binding site with only two (not three) ion densities remaining; (2) in Na+ solution the selectivity filter remains intact with ion density in each binding site rather than collapsing; (3) the C-type inactivated W366F channel in Na+ shows highly variable conformation and only low-resolution structure.","method":"Cryo-EM structure determination in multiple functional states","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — near-atomic resolution cryo-EM structures in four distinct functional states with direct visualization of ion occupancy and toxin interaction","pmids":["39945513"],"is_preprint":false},{"year":2019,"finding":"Sigma-1 receptor (Sig-1R) interacts with Kv1.2 in baseline conditions in HEK293 cells to influence bimodal activation gating; ligand activation of Sig-1R modulates Kv1.2 current amplitude; Kvβ2 occludes the Sig-1R–Kv1.2 interaction; the ALS16-associated Sig-1R-E102Q mutation abolishes Sig-1R modulation of Kv1.2, implicating E102 as critical for the interaction.","method":"Patch clamp electrophysiology, co-transfection in HEK293 cells, pharmacological Sig-1R ligands, dominant-negative mutation","journal":"Physiological reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional electrophysiology with pharmacological and genetic dissection, single lab; direct binding not shown","pmids":["31222975"],"is_preprint":false},{"year":2018,"finding":"MBD1 represses Kcna2 gene expression by recruiting DNA methyltransferase DNMT3a to the Kcna2 promoter in DRG neurons; MBD1-deficient mice show blunted nerve injury-induced pain hypersensitivity and DRG overexpression of MBD1 produces pain hypersensitivity; DRG MBD1 deficiency reduces acute pain responses.","method":"ChIP assay for DNMT3a recruitment to Kcna2 promoter, MBD1 knockout mice, AAV overexpression, behavioral pain assays","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus genetic KO plus OE with behavioral readout, single lab","pmids":["30266739"],"is_preprint":false},{"year":2023,"finding":"Transcription factor EBF1 directly binds the Kcna2 gene promoter and activates its transcription in DRG neurons; CCI-induced EBF1 downregulation decreases EBF1 binding to the Kcna2 promoter and reduces Kv1.2 expression; AAV-mediated EBF1 rescue restores Kv1.2 expression and attenuates neuropathic pain, while EBF1 knockdown reduces Kv1.2 and causes pain hypersensitivity.","method":"ChIP assay, luciferase reporter assay, AAV overexpression/knockdown, western blot, behavioral pain assays","journal":"Translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay establish direct promoter binding; functional consequences shown bidirectionally; single lab","pmids":["37607607"],"is_preprint":false},{"year":2024,"finding":"BCAA deficiency activates expression of L-type amino acid transporter 1 (LAT1/Slc7a5) through ATF4 in DRG neurons; abnormally upregulated LAT1 reduces Kv1.2 localization to the cell membrane and inhibits Kv1.2 channels, increasing neuronal excitability and causing diabetic neuropathic pain symptoms; LAT1 inhibition alleviates these symptoms.","method":"RNA sequencing, label-free quantitative proteomics, patch clamp, immunostaining for membrane localization, LAT1 inhibitor treatment in mice","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics plus electrophysiology plus in vivo rescue, single lab, mechanism via LAT1 = Slc7a5 consistent with prior Slc7a5-Kv1.2 literature","pmids":["38946582"],"is_preprint":false},{"year":2010,"finding":"A missense mutation I402T in the S6 segment of Kv1.2 (in Pingu mice) dramatically decreases the amount of functional Kv1 channels in cerebellar basket cell terminals without major changes in biophysical properties; this results in increased frequency and amplitude of spontaneous GABAergic IPSCs and reduced Purkinje cell firing, causing motor incoordination, which is partially rescued by acetazolamide or Kcna2 transgenic complementation.","method":"ENU mutagenesis screen, patch clamp in cerebellar slices, immunochemistry, CHO cell expression, transgenic complementation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mouse model with defined mutation plus electrophysiology in native tissue plus expression analysis plus transgenic rescue","pmids":["20696761"],"is_preprint":false},{"year":1993,"finding":"TsTX-Kα and α-dendrotoxin competitively block Kv1.2 K+ channels by binding to the same or closely related extracellular sites; TsTX-Kα blocks with Kd ~0.21 nM (10-fold more potent than DTX at 2.8 nM); TsTX-Kα does not affect kinetics or voltage dependence of activation; 4-AP blockade is unaffected by TsTX-Kα, indicating a distinct binding site for 4-AP.","method":"Whole-cell and patch-clamp recordings from B82 fibroblasts stably expressing Kv1.2, competitive binding analysis","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — competitive pharmacological dissection with multiple toxins in defined heterologous expression system","pmids":["8355670"],"is_preprint":false},{"year":2015,"finding":"Kv1.2 downregulation in distal apical dendrites of CA3 pyramidal cells mediates mossy fiber-induced heterosynaptic LTP of perforant path (PP) EPSPs: Kv1.2 is polarized to distal apical dendrites; its downregulation specifically enhances PP-evoked EPSPs by facilitating activation of dendritic Na+ channels at distal dendrites; partial block of dendritic Na+ channels reverses the enhanced PP-EPSPs.","method":"Patch clamp, immunostaining for subcellular Kv1.2 distribution, compartmental simulations, TTX application in hippocampal slices","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology plus immunostaining plus computational modeling, single lab","pmids":["26047212"],"is_preprint":false}],"current_model":"Kv1.2 (KCNA2) is a voltage-gated K+ channel whose crystal/cryo-EM structures establish that independent voltage-sensor domains couple to the pore via S4-S5 linker helices, gating charge is carried principally by the first S4 arginine, and toxins such as dendrotoxin and TsTX-Kα block the channel by occluding the extracellular pore mouth; channel function and surface expression are tuned by PKA-mediated phosphorylation at Ser-449, C-terminal cluster phosphorylation at Ser-440/441, N-linked glycosylation, and by dynamic interactions with cortactin (linking Kv1.2 to the actin cytoskeleton and endocytic machinery), RPTPα (reversing tyrosine kinase-mediated suppression), Kvβ subunits, Slc7a5, and sigma-1 receptor; in neurons Kv1.2 suppresses presynaptic hyperexcitability, regulates subthreshold excitability and state transitions, undergoes activity-dependent endocytosis from distal dendrites to enable intrinsic plasticity, and its expression is epigenetically silenced after nerve injury by DNMT3a, DNMT1, G9a, and MBD1-recruited methylation of the Kcna2 promoter, with transcription factor EBF1 directly activating Kcna2 transcription."},"narrative":{"mechanistic_narrative":"KCNA2 encodes Kv1.2, a voltage-gated potassium channel that sets neuronal excitability across somatic, axonal, presynaptic, and dendritic compartments, where it suppresses hyperexcitability and tunes state transitions [PMID:8046438, PMID:12777451, PMID:13679409]. Atomic-resolution crystal and multi-state cryo-EM structures establish that independent voltage-sensor domains perform mechanical work on the pore through the S4-S5 linker, that gating charge (~10 e0) is carried principally by the first S4 arginine, and that pore-blocking toxins occlude the extracellular pore mouth — α-dendrotoxin inserting a lysine into the selectivity filter and displacing the outermost ion site [PMID:16002579, PMID:25779871, PMID:39945513, PMID:8355670]. Channel gating shows distinctive bimodal and use-dependent activation governed by the S2-S3 linker residue T252 and by cytoplasmic and extracellular redox-sensitive regulators [PMID:17766348, PMID:25716850, PMID:28831076]. Surface expression and function are tuned by phosphorylation: PKA acts at Ser-449 and a C-terminal cluster (Ser-440/441) marks post-ER, surface channels and controls trafficking, while N-linked glycosylation promotes forward trafficking and stabilizes internalized channel [PMID:18056633, PMID:19389710, PMID:27377235]. Kv1.2 activity is further set by a network of accessory and signaling partners — cortactin, which links the channel to actin and the endocytic machinery and is required for activity-dependent internalization; RPTPα, which opposes tyrosine-kinase-mediated current suppression downstream of muscarinic receptors; the amino acid transporter Slc7a5, which strongly hyperpolarizes activation and reduces channel protein; Kvβ subunits; and sigma-1 receptor [PMID:12151401, PMID:17959782, PMID:9878055, PMID:30356053, PMID:31222975]. In neurons this regulation underlies intrinsic plasticity, as activity-dependent endocytosis of Kv1.2 from distal CA3 dendrites produces long-term potentiation of intrinsic excitability and heterosynaptic potentiation [PMID:23981714, PMID:26047212]. After peripheral nerve injury, Kcna2 is epigenetically silenced in DRG neurons through promoter methylation by DNMT3a, DNMT1, the histone methyltransferase G9a, MBD1-recruited DNMT3a, and an antisense lncRNA, while the transcription factor EBF1 directly activates Kcna2 transcription; loss of channel expression increases neuronal excitability and drives neuropathic pain [PMID:28270689, PMID:31182635, PMID:27874088, PMID:30266739, PMID:23792947, PMID:37607607]. De novo KCNA2 mutations cause epileptic encephalopathy through either dominant-negative loss-of-function or gain-of-function mechanisms [PMID:25751627].","teleology":[{"year":1993,"claim":"Establishing how peptide toxins block Kv1.2 provided the pharmacological tools needed to isolate Kv1.2-mediated currents in native tissue.","evidence":"Competitive binding and patch-clamp with TsTX-Kα and α-dendrotoxin on B82 cells stably expressing Kv1.2","pmids":["8355670"],"confidence":"High","gaps":["Did not resolve the structural basis of toxin occlusion","Did not address channel function in vivo"]},{"year":1994,"claim":"Mapping where Kv1.2 protein resides established that the channel occupies distinct neuronal compartments in a cell-type-specific manner, implying compartment-specific roles.","evidence":"Immunocytochemistry, in situ hybridization, and subcellular fractionation in mouse and rat brain","pmids":["8046438","8158277"],"confidence":"High","gaps":["Mechanism of differential targeting unresolved","Functional consequence of each localization not tested"]},{"year":1999,"claim":"Identifying RPTPα as a Kv1.2-associated phosphatase explained how GPCR-driven tyrosine phosphorylation suppression of the channel is reversed.","evidence":"mAChR-dependent co-IP, in vitro binding, and Xenopus oocyte electrophysiology","pmids":["9878055"],"confidence":"High","gaps":["Specific tyrosine residues targeted not fully defined here","Endogenous neuronal relevance not directly shown"]},{"year":2002,"claim":"Discovery of a direct cortactin-Kv1.2 interaction linked the channel to the actin cytoskeleton and to phosphorylation-dependent regulation of current.","evidence":"Purified recombinant protein binding, reciprocal co-IP, mutagenesis, and electrophysiology in HEK293 cells","pmids":["12151401"],"confidence":"High","gaps":["Did not yet define cortactin's role in trafficking versus current","In vivo neuronal requirement not established"]},{"year":2003,"claim":"Functional dissection in presynaptic terminals and striatal neurons established Kv1.2 as a suppressor of hyperexcitability and a regulator of subthreshold state transitions.","evidence":"Selective toxin pharmacology and paired/current-clamp recordings in calyx of Held and striatal slices","pmids":["12777451","13679409"],"confidence":"High","gaps":["Heteromeric subunit composition only partially defined","Upstream signals controlling channel availability not addressed"]},{"year":2005,"claim":"The Kv1.2 crystal structure resolved the long-standing question of how voltage sensors mechanically couple to the pore.","evidence":"X-ray crystallography at 2.9 Å of the mammalian channel","pmids":["16002579"],"confidence":"High","gaps":["Captured a single (open) conformation","Did not resolve inactivated or toxin-bound states"]},{"year":2007,"claim":"Identification of C-terminal phosphosites, gating-mode switches, and a glycosylation requirement showed that Kv1.2 surface expression and gating are post-translationally controlled.","evidence":"Tandem MS phosphosite mapping from brain, mutagenesis, surface assays, glycosidase treatment, and patch clamp including chimera/T252 analysis","pmids":["18056633","17324383","17766348"],"confidence":"High","gaps":["Kinases and phosphatases for the C-terminal cluster not all identified","Cytoplasmic regulator of slow gating mode unidentified"]},{"year":2007,"claim":"cAMP/PKA signaling was shown to bidirectionally tune Kv1.2 surface levels through opposing trafficking pathways and endocytic machinery engaging cortactin.","evidence":"Surface biotinylation with PKA/endocytosis inhibitors and cortactin gene replacement with FRET and endocytosis assays","pmids":["18003609","17959782"],"confidence":"High","gaps":["Molecular identity of PKA-independent pathway not defined","Link between specific phosphosites and endocytosis incomplete"]},{"year":2009,"claim":"Pinpointing Ser-449 as the functionally critical PKA site connected PKA signaling directly to a defined molecular event on the channel.","evidence":"In vitro/in situ phosphorylation, MS, S449A mutagenesis, and patch clamp","pmids":["19389710"],"confidence":"High","gaps":["Whether Ser-449 acts through trafficking or gating in neurons not fully resolved"]},{"year":2010,"claim":"A spontaneous S6 mutation in mice demonstrated that reduced functional Kv1.2 in basket cell terminals causes motor incoordination, linking channel availability to circuit output.","evidence":"ENU-derived Pingu mouse, cerebellar slice patch clamp, immunochemistry, and transgenic complementation","pmids":["20696761"],"confidence":"High","gaps":["Mechanism by which I402T reduces functional channel number unclear","Human relevance not addressed at the time"]},{"year":2013,"claim":"Activity-dependent Kv1.2 internalization was identified as a substrate for intrinsic plasticity, and sigma-1 receptor and D2 autoreceptor partnerships placed Kv1.2 in neuromodulatory signaling.","evidence":"Kv1.2 KO mice with endocytosis/PTK inhibitors and dendritic Ca2+ imaging; co-IP and electrophysiology for Sig-1R and D2-AR in striatal tissue","pmids":["23981714","23332758","21233214"],"confidence":"High","gaps":["Precise endocytic adaptors recruiting Kv1.2 not fully defined","Direct versus indirect nature of Sig-1R association left open"]},{"year":2013,"claim":"Discovery of a Kcna2 antisense lncRNA established transcriptional/RNA-level silencing as a driver of injury-induced Kv1.2 loss and neuropathic pain.","evidence":"MZF1 promoter binding assays, expression manipulation, patch clamp, and behavioral pain assays in DRG","pmids":["23792947"],"confidence":"Medium","gaps":["Single-lab characterization","Relationship to DNA-methylation silencing not integrated"]},{"year":2015,"claim":"Linking de novo KCNA2 mutations to epileptic encephalopathy via two opposite biophysical mechanisms established the channel as a Mendelian disease gene.","evidence":"Next-generation sequencing and two-electrode voltage-clamp functional characterization of mutant channels","pmids":["25751627"],"confidence":"High","gaps":["Genotype-phenotype determinants beyond gain/loss dichotomy incomplete","In vivo consequences in neurons not directly modeled here"]},{"year":2015,"claim":"Use-dependent activation and dendritic Kv1.2 downregulation were shown to confer unique gating behavior and to mediate heterosynaptic potentiation, refining Kv1.2's role in dendritic computation.","evidence":"Patch clamp in HEK and hippocampal neurons; immunostaining, compartmental modeling, and TTX in slices","pmids":["25716850","26047212","25779871"],"confidence":"High","gaps":["Molecular basis of use-dependent activation not fully resolved","Single-lab dendritic studies"]},{"year":2017,"claim":"DNA methyltransferases and histone methyltransferase G9a were identified as effectors silencing Kcna2 after nerve injury, defining an epigenetic axis driving neuropathic pain.","evidence":"Methylation assays, reporter assays, siRNA/AAV manipulation, patch clamp, and behavioral assays in DRG (DNMT3a, DNMT1, G9a)","pmids":["28270689","31182635","27874088"],"confidence":"High","gaps":["Hierarchy among DNMT3a, DNMT1, and G9a not fully ordered","Some studies single-lab and Medium confidence"]},{"year":2018,"claim":"Identification of Slc7a5 as a Kv1.2 complex partner revealed a powerful gating and protein-level regulator with direct relevance to epilepsy mutants.","evidence":"MS interactome, patch clamp, western blot, and co-expression with wild-type and disease-mutant channels (and Slc3a2)","pmids":["30356053"],"confidence":"High","gaps":["Structural basis of the Kv1.2-Slc7a5 interaction unknown","Endogenous neuronal stoichiometry not defined"]},{"year":2018,"claim":"MBD1 was shown to recruit DNMT3a to the Kcna2 promoter, providing the reader/effector link in injury-induced epigenetic silencing.","evidence":"ChIP for DNMT3a recruitment, MBD1 KO mice, AAV overexpression, and pain behavior","pmids":["30266739"],"confidence":"Medium","gaps":["Single-lab study","Direct effect on channel protein not measured"]},{"year":2019,"claim":"Demonstrating sigma-1 receptor modulation of bimodal Kv1.2 gating, including an ALS16 mutation that abolishes it, connected channel gating to a disease-relevant receptor.","evidence":"Patch clamp, co-transfection, Sig-1R ligands, and the E102Q dominant-negative mutation in HEK293 cells","pmids":["31222975"],"confidence":"Medium","gaps":["Direct binding not demonstrated","Single-lab heterologous system"]},{"year":2020,"claim":"Showing convergent regulation of Kv1.2 by Slc7a5 and Kvβ1.2 clarified how accessory subunits jointly shape availability and inactivation.","evidence":"Whole-cell patch clamp and western blot with co-transfected subunit combinations in HEK cells","pmids":["32311044"],"confidence":"Medium","gaps":["Single-lab","Native neuronal relevance of triple-partner regulation untested"]},{"year":2023,"claim":"Identifying EBF1 as a direct activator of Kcna2 transcription provided the positive regulatory counterpart to injury-induced silencing.","evidence":"ChIP, luciferase reporter, AAV overexpression/knockdown, and pain behavior in DRG","pmids":["37607607"],"confidence":"Medium","gaps":["Single-lab","Interplay with repressive epigenetic machinery not resolved"]},{"year":2024,"claim":"Linking BCAA deficiency to ATF4-driven LAT1/Slc7a5 upregulation extended Slc7a5-mediated Kv1.2 suppression to diabetic neuropathic pain in vivo.","evidence":"RNA-seq, quantitative proteomics, patch clamp, membrane-localization imaging, and LAT1 inhibitor treatment in mice","pmids":["38946582"],"confidence":"Medium","gaps":["Single-lab","Whether effect is purely via Slc7a5 not fully isolated"]},{"year":2025,"claim":"Multi-state cryo-EM structures resolved how Kv1.2 inactivates, conducts ions, and is blocked by dendrotoxin at atomic detail.","evidence":"Cryo-EM in open, C-type inactivated, dendrotoxin-blocked, and Na+-bound states","pmids":["39945513"],"confidence":"High","gaps":["C-type inactivated W366F state only low-resolution","Structures of accessory-partner complexes not determined"]},{"year":null,"claim":"How the many post-translational, accessory-protein, and transcriptional regulators of Kv1.2 are integrated in a single compartmentalized neuron, and the structural basis of partner interactions, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of Kv1.2 with Slc7a5, cortactin, or sigma-1 receptor","Integration of competing trafficking/silencing pathways in vivo not established","Mechanism of redox- and cytoplasm-dependent gating-mode switching unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,7,26,28,30]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,6,12,29,34]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[6,9,29]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[4,5]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[7,14,26,37]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,12,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16,17,27,35]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[6,10,29]}],"complexes":[],"partners":["KCNA1","KCNA5","CTTN","PTPRA","SLC7A5","KCNAB2","SIGMAR1","DRD2"],"other_free_text":[]}},"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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The authors hypothesize this arises from association with different heterologous subunits in different cell types.\",\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 / Strong — direct immunolocalization with cell-type resolution; independently replicated across multiple labs\",\n      \"pmids\": [\"8158277\"],\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 acetylcholine receptor (mAChR)-dependent manner; N- and C-termini of Kv1.2 bind RPTPalpha in vitro; overexpression of RPTPalpha increases resting Kv1.2 current and reverses tyrosine kinase-induced phosphorylation and suppression of Kv1.2 current, establishing RPTPalpha as a phosphatase that opposes GPCR-mediated channel suppression.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay, Xenopus oocyte electrophysiology, biochemical phosphorylation analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP plus in vitro binding plus functional electrophysiology in multiple systems\",\n      \"pmids\": [\"9878055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Kv1.2 associates with the actin-binding protein cortactin; this interaction is direct (shown with purified recombinant proteins), requires a 19-amino acid span in the Kv1.2 C-terminus, and is attenuated by tyrosine phosphorylation of specific C-terminal tyrosines. M1 muscarinic receptor activation reduces cortactin-Kv1.2 interaction, and mutant Kv1.2 channels deficient in cortactin binding exhibit strongly attenuated ionic 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 / Strong — direct binding with purified proteins plus functional validation, reciprocal co-IP, site-directed mutagenesis\",\n      \"pmids\": [\"12151401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cortactin is required for Kv1.2 regulation: pull-down assays confirmed direct interaction reduced by tyrosine phosphorylation of Kv1.2; FRET demonstrated in vivo interaction; cortactin's fourth repeat actin-binding domain and N-terminal Arp2/3-binding region (but not the dynamin-binding SH3 domain) are critical for Kv1.2 endocytosis; manipulating the cortactin-binding site within Kv1.2 confirms cortactin proximity influences channel function.\",\n      \"method\": \"Pull-down with recombinant proteins, FRET, flow cytometry, cortactin gene replacement, endocytosis assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including FRET, pull-down, mutagenesis, functional assay\",\n      \"pmids\": [\"17959782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A cluster of cytoplasmic C-terminal phosphorylation sites (pS434, pS440, pS441, pS449) on Kv1.2 regulates its trafficking. Phosphorylation at pS440/pS441 is present only on post-ER/cell-surface Kv1.2, not on newly synthesized ER-localized channel; elimination of these sites by mutation reduces cell-surface expression and functional expression. pS449 phosphorylation regulates pS440/pS441 phosphorylation. These mutations also suppress trafficking of Kv1.2/Kv1.4 heteromeric channels.\",\n      \"method\": \"Tandem MS of Kv1.2 purified from rat/human/mouse brain, site-directed mutagenesis, cell-surface expression assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo phosphosite identification by MS from multiple species combined with mutagenesis and functional validation\",\n      \"pmids\": [\"18056633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In the calyx of Held presynaptic terminal, Kv1.2 homomers are responsible for two-thirds of the presynaptic low-threshold K+ current, while Kv1.1/Kv1.2 heteromers contribute the remaining current. Kv1.2 channels are located in the transition zone between the axon and synaptic terminal. Blocking Kv1.2 (with TsTX-Kα) increases the depolarizing after-potential amplitude following each action potential, bringing the terminal closer to threshold and evoking additional EPSCs in postsynaptic cells, establishing Kv1.2 as a suppressor of presynaptic terminal hyperexcitability.\",\n      \"method\": \"Selective toxin pharmacology (TsTX-Kα, DTX-K), current-clamp and voltage-clamp recordings from calyx of Held, paired pre/postsynaptic recordings\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — selective pharmacology with multiple toxins, direct pre/postsynaptic paired recordings, defined functional readout\",\n      \"pmids\": [\"12777451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The Kv1.2 α-subunit comprises the O2-sensitive K+ channel in PC12 cells: intracellularly dialyzed anti-Kv1.2 antibody completely blocked the O2-sensitive K+ current, whereas anti-Kv2.1 antibody had no effect; recombinant Kv1.2 expressed in Xenopus oocytes was inhibited by hypoxia, while Kv2.1 was not, establishing Kv1.2 as the molecular substrate of the hypoxic K+ current.\",\n      \"method\": \"Intracellular antibody dialysis, Xenopus oocyte expression, Western blot, whole-cell voltage clamp\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — intracellular antibody occlusion plus recombinant expression, two independent functional approaches\",\n      \"pmids\": [\"10790158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"N-glycosylation state of Kv1.2 affects its gating (V1/2 shifts, activation/deactivation kinetics, C-type inactivation) via a surface potential mechanism, and preventing N-glycosylation decreases cell-surface Kv1.2 expression by ~40% primarily through partial ER retention; this trafficking defect is rescued by co-expression with glycosylated Kv1.4 but not Kvβ2.\",\n      \"method\": \"Site-directed mutagenesis, whole-cell patch clamp, glycosidase treatment, confocal imaging, western blot\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus functional electrophysiology plus trafficking assays, single lab\",\n      \"pmids\": [\"17324383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"cAMP regulates Kv1.2 surface levels through two opposing trafficking pathways: a PKA-dependent pathway controlling steady-state channel turnover (basal PKA activity promotes endocytosis), and a PKA-independent pathway that elevates surface Kv1.2 by inhibiting endocytosis when cAMP is elevated above basal.\",\n      \"method\": \"Surface biotinylation, pharmacological inhibitors of PKA, endocytosis inhibitors, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — surface expression assays with multiple pharmacological tools, single lab\",\n      \"pmids\": [\"18003609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PKA phosphorylates Kv1.2 specifically at Ser-449 in the C-terminus; in vitro and in situ phosphorylation at this site were confirmed by MS; PKA-induced increase in Kv1.2 current amplitude is abolished by the S449A mutation, establishing Ser-449 as the functionally critical PKA phosphorylation site for channel regulation.\",\n      \"method\": \"In vitro phosphorylation, MALDI-TOF MS, MS/MS, site-directed mutagenesis, whole-cell and inside-out patch clamp\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical phosphosite identification by MS combined with mutagenesis and functional electrophysiology in multiple configurations\",\n      \"pmids\": [\"19389710\"],\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, caused by persistent protein-protein association between Sig-1Rs and Kv1.2 channels, associated with redistribution of both proteins from intracellular compartments to the plasma membrane.\",\n      \"method\": \"Co-immunoprecipitation in striatal tissue, ex vivo and in vitro electrophysiology, subcellular fractionation, behavioral cocaine response assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP in native tissue plus electrophysiology plus localization, multiple orthogonal methods\",\n      \"pmids\": [\"23332758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Kv1.2 contributes to D2 dopamine autoreceptor (D2-AR) regulation of axonal dopamine overflow: selective Kv1.2 blockade and Kv1.2 knockout both attenuate D2-AR-mediated inhibition of DA overflow; D2-AR activation increases Kv1.2 currents in co-transfected cells via Gβγ subunit signaling; D2-AR and Kv1.2 physically associate in striatal tissue by immunoprecipitation.\",\n      \"method\": \"Fast-scan cyclic voltammetry in striatal slices, Kv1.2 KO mice, selective toxin blockade, electrophysiology, immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus pharmacology plus co-IP in native tissue plus functional electrophysiology\",\n      \"pmids\": [\"21233214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Activity-dependent downregulation of Kv1.2 in hippocampal CA3 pyramidal cells underlies long-term potentiation of intrinsic excitability (LTP-IE): a conditioning train of 20 APs at 10 Hz causes persistent reduction in D-type K+ current; LTP-IE is abolished by inhibition of endocytosis or protein tyrosine kinase, and is absent in Kv1.2 knockout mice, indicating it is mediated by internalization of Kv1.2 from distal apical dendrites triggered by back-propagating AP-induced dendritic Ca2+ signaling.\",\n      \"method\": \"Whole-cell patch clamp, endocytosis inhibitors, PTK inhibitors, Kv1.2 KO mice, dendritic Ca2+ imaging\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO controls plus pharmacology plus electrophysiology with defined cellular mechanism\",\n      \"pmids\": [\"23981714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Secretin decreases cell-surface Kv1.2 levels in rat cerebellar slices by modulating Kv1.2 endocytic trafficking; this effect is mimicked by adenylate cyclase activation (forskolin) and blocked by pharmacological inhibitors of AC or PKA, localizing the effect to basket cell axon terminals and Purkinje cell dendrites. Intra-cerebellar infusion of a Kv1.2 inhibitor or secretin both enhance acquisition of eyeblink conditioning.\",\n      \"method\": \"Cell-surface protein biotinylation, pharmacological inhibitors, cerebellar slice imaging, behavioral eyeblink conditioning\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biotinylation trafficking assay plus behavioral readout, single lab\",\n      \"pmids\": [\"22764231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"De novo mutations in KCNA2 cause epileptic encephalopathy through two distinct mechanisms: dominant-negative loss-of-function (almost complete current reduction) causing multifocal epileptiform discharges and focal seizures, or gain-of-function (permanently open channels with drastic negative shift in activation) causing a more severe encephalopathy with generalized seizures, as established by functional electrophysiology of the mutant channels.\",\n      \"method\": \"Xenopus oocyte two-electrode voltage clamp, next-generation sequencing, functional expression of mutant channels\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct functional characterization of multiple mutants in heterologous expression system with clear genotype-phenotype correlation replicated in follow-up cohort studies\",\n      \"pmids\": [\"25751627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DNA methyltransferase DNMT3a represses Kcna2 expression by methylating the Kcna2 promoter region in DRG neurons after nerve injury; blocking DNMT3a prevents nerve injury-induced methylation of the Kcna2 promoter, rescues Kcna2 expression and Kv current, and attenuates neuropathic pain. Mimicking DNMT3a upregulation reduces Kcna2 promoter activity, Kcna2 expression, and Kv current and causes neuropathic pain symptoms.\",\n      \"method\": \"Chromatin methylation assay, luciferase reporter assay, siRNA knockdown, AAV overexpression, patch clamp, behavioral pain assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional manipulation (KD and OE) with molecular mechanism (promoter methylation), functional electrophysiology, and behavioral readout\",\n      \"pmids\": [\"28270689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"G9a (euchromatic histone-lysine N-methyltransferase 2) epigenetically silences Kcna2 in injured DRG neurons: blocking nerve injury-induced G9a increase rescues Kcna2 mRNA and protein expression; mimicking the increase decreases Kcna2 expression, reduces Kv current, and increases DRG neuronal excitability. G9a mRNA is co-localized with Kcna2 mRNA in DRG neurons.\",\n      \"method\": \"siRNA, AAV-mediated overexpression, western blot, qPCR, patch clamp, immunofluorescence\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation with functional electrophysiology, single lab\",\n      \"pmids\": [\"27874088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DNMT1, acting as a de novo methyltransferase, represses Kcna2 expression by increasing DNA methylation within the promoter and 5'-UTR of the Kcna2 gene in injured DRG, downstream of CREB-mediated Dnmt1 transcriptional activation; blocking DNMT1 upregulation prevents Kcna2 methylation, rescues Kv current and reduces DRG neuronal hyperexcitability.\",\n      \"method\": \"CREB knockout/overexpression, DNMT1 siRNA, bisulfite sequencing of Kcna2 promoter, patch clamp, behavioral assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter methylation analysis plus functional electrophysiology, single lab\",\n      \"pmids\": [\"31182635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Kv1.2 channels exhibit two distinct activation gating modes ('fast' and 'slow') switchable by a prepulse; the S2-S3 linker threonine residue (T252) acts as a switch between these modes — introduction of a positive charge at this position abolishes 'slow' activation gating; cytoplasm dialysis or patch excision also switches gating from slow to fast, implicating cytoplasmic regulators.\",\n      \"method\": \"Whole-cell and inside-out patch clamp, chimera construction between Kv1.2 and Kv1.5, point mutagenesis, cytoplasm dialysis\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis plus chimera analysis plus multiple electrophysiology configurations in single rigorous study\",\n      \"pmids\": [\"17766348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The dominant form of vascular delayed rectifier K+ channel in rabbit portal vein myocytes involves heteromultimeric association of Kv1.2 and Kv1.5 subunits: native K(DR) properties including 4-AP-induced positive shift in voltage dependence of activation are reproduced by Kv1.5/Kv1.2 heteromers or tandem constructs but not by Kv1.5 homotetramers alone; native K(DR) was insensitive to charybdotoxin (which blocks Kv1.2 homomers), consistent with heteromeric composition.\",\n      \"method\": \"Patch clamp, expression of heteromeric and tandem-linked channel constructs in mammalian cells, pharmacological profiling\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional comparison of native vs recombinant heteromeric channels, single lab\",\n      \"pmids\": [\"11717161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Slc7a5, a neutral amino acid transporter, forms a multi-protein complex with Kv1.2 (identified by mass spectrometry), dramatically hyperpolarizes Kv1.2 voltage-dependence of activation by -47 mV, reduces total Kv1.2 protein, and accelerates inactivation causing channels to accumulate in a non-conducting state. Slc3a2 (a known Slc7a5 binding partner) attenuates these effects. Epilepsy-linked gain-of-function Kv1.2 mutants show enhanced sensitivity to Slc7a5.\",\n      \"method\": \"Mass spectrometry interactome screen followed by patch clamp, western blot, co-expression with wild-type and disease mutant channels\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS identification plus functional electrophysiology with multiple mutants, mechanistic pathway placement, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30356053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Slc7a5 regulates Kv1.2 in the presence of Kvβ1.2: Slc7a5-induced suppression of Kv1.2 current and protein is attenuated by Kvβ1.2 co-expression, but gating effects of Slc7a5 (disinhibition, hyperpolarizing shift) persist alongside Kvβ-mediated inactivation. Slc7a5 also accelerates Kvβ-induced inactivation, shifts steady-state inactivation, and delays recovery, indicating convergent regulation by both accessory proteins.\",\n      \"method\": \"Whole-cell patch clamp, western blot, co-transfection in HEK cells\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional electrophysiology with multiple subunit combinations, single lab\",\n      \"pmids\": [\"32311044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Kv1.2 exhibits unique use-dependent activation during trains of brief depolarizations (arising from prepulse potentiation); this property is not shared by other Kv1 subtypes but is conferred in heteromeric channel complexes containing even a single Kv1.2 subunit; use-dependent activation is observed in mammalian cell lines and primary hippocampal neurons.\",\n      \"method\": \"Whole-cell patch clamp in HEK cells and primary hippocampal neuron cultures, heteromeric channel co-expression\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology in multiple cell systems with defined subunit composition, single lab\",\n      \"pmids\": [\"25716850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Extracellular redox environment regulates Kv1.2 gating mode: reducing agents promote a shift to an 'inhibited' gating mode that resists opening and causes pronounced use-dependent activation; this redox sensitivity is absent in other Kv1 channels but is apparent in heteromeric channels containing Kv1.2 subunits; mutagenesis of candidate cysteines fails to abolish redox sensitivity, suggesting an extrinsic redox-sensitive binding partner.\",\n      \"method\": \"Whole-cell patch clamp, reducing agent application, site-directed mutagenesis of cysteine residues, heteromeric channel expression\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological manipulation plus mutagenesis plus heteromeric channels, single lab; mechanism of redox sensing remains partially unresolved\",\n      \"pmids\": [\"28831076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Kv1.2-containing channels in striatal medium spiny neurons activate rapidly near resting potential (~-60 mV), inactivate slowly, and account for ~50% of subthreshold K+ current; pharmacological blockade (by tityustoxin-Kα but not by toxins lacking high Kv1.2 affinity) reduces first-spike latency and increases discharge frequency from hyperpolarized membrane potentials, establishing Kv1.2 as a regulator of state transitions in these neurons.\",\n      \"method\": \"Whole-cell patch clamp, selective toxin pharmacology, current-clamp in acute slices, RT-PCR\",\n      \"journal\": \"Journal of neurophysiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — selective toxin profiling with multiple blockers plus functional current-clamp recordings in acute slices\",\n      \"pmids\": [\"13679409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The lncRNA Kcna2 antisense RNA silences Kcna2 expression in DRG primary afferent neurons; its increase after peripheral nerve injury (via activation of transcription factor MZF1 binding to the antisense RNA gene promoter) downregulates Kcna2 mRNA and protein, reduces total voltage-gated K+ current, increases DRG neuron excitability, and produces neuropathic pain. Blocking the antisense RNA increase reverses these effects.\",\n      \"method\": \"Promoter binding assay (ChIP/EMSA for MZF1), siRNA/overexpression, patch clamp, behavioral pain assays\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway from lncRNA to Kcna2 expression to K+ current to behavior; note this is about Kcna2 regulation, not the protein mechanism per se; single lab\",\n      \"pmids\": [\"23792947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Kv1.2 gating charge is ~10 elementary charges, approximately 25% less than Shaker; neutralization of R1 in the S4 segment decreases voltage sensitivity to ~50% of wild-type, while subsequent arginines have much smaller effects — in contrast to Shaker where the first four basic residues contribute roughly equally, suggesting the VSD septum separating aqueous crevices in Kv1.2 may be thicker than in Shaker.\",\n      \"method\": \"Two-electrode voltage clamp in Xenopus oocytes, gating current measurements, S4 arginine neutralization mutagenesis\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct gating charge measurement combined with systematic mutagenesis of S4 residues\",\n      \"pmids\": [\"25779871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"N-linked glycosylation of Kv1.2 at the conserved S1-S2 linker site facilitates forward trafficking to the cell membrane and enhances stability of internalized channels by reducing their degradation rate; removal of sialic acids from surface Kv1.2 accelerates degradation of internalized channels.\",\n      \"method\": \"Glycosidase treatment, N-glycosylation mutants, surface biotinylation, protein half-life assays in COS-7 cells and hippocampal neurons\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus glycosidase treatment plus trafficking assays, single lab\",\n      \"pmids\": [\"27377235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CryoEM structures of Kv1.2 at near-atomic resolution 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: (1) dendrotoxin lysine penetrates into the selectivity filter coordinated by carbonyls, displacing the outermost ion-binding site with only two (not three) ion densities remaining; (2) in Na+ solution the selectivity filter remains intact with ion density in each binding site rather than collapsing; (3) the C-type inactivated W366F channel in Na+ shows highly variable conformation and only low-resolution structure.\",\n      \"method\": \"Cryo-EM structure determination in multiple functional states\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — near-atomic resolution cryo-EM structures in four distinct functional states with direct visualization of ion occupancy and toxin interaction\",\n      \"pmids\": [\"39945513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Sigma-1 receptor (Sig-1R) interacts with Kv1.2 in baseline conditions in HEK293 cells to influence bimodal activation gating; ligand activation of Sig-1R modulates Kv1.2 current amplitude; Kvβ2 occludes the Sig-1R–Kv1.2 interaction; the ALS16-associated Sig-1R-E102Q mutation abolishes Sig-1R modulation of Kv1.2, implicating E102 as critical for the interaction.\",\n      \"method\": \"Patch clamp electrophysiology, co-transfection in HEK293 cells, pharmacological Sig-1R ligands, dominant-negative mutation\",\n      \"journal\": \"Physiological reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional electrophysiology with pharmacological and genetic dissection, single lab; direct binding not shown\",\n      \"pmids\": [\"31222975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MBD1 represses Kcna2 gene expression by recruiting DNA methyltransferase DNMT3a to the Kcna2 promoter in DRG neurons; MBD1-deficient mice show blunted nerve injury-induced pain hypersensitivity and DRG overexpression of MBD1 produces pain hypersensitivity; DRG MBD1 deficiency reduces acute pain responses.\",\n      \"method\": \"ChIP assay for DNMT3a recruitment to Kcna2 promoter, MBD1 knockout mice, AAV overexpression, behavioral pain assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus genetic KO plus OE with behavioral readout, single lab\",\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 transcription in DRG neurons; CCI-induced EBF1 downregulation decreases EBF1 binding to the Kcna2 promoter and reduces Kv1.2 expression; AAV-mediated EBF1 rescue restores Kv1.2 expression and attenuates neuropathic pain, while EBF1 knockdown reduces Kv1.2 and causes pain hypersensitivity.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, AAV overexpression/knockdown, western blot, behavioral pain assays\",\n      \"journal\": \"Translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay establish direct promoter binding; functional consequences shown bidirectionally; single lab\",\n      \"pmids\": [\"37607607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BCAA deficiency activates expression of L-type amino acid transporter 1 (LAT1/Slc7a5) through ATF4 in DRG neurons; abnormally upregulated LAT1 reduces Kv1.2 localization to the cell membrane and inhibits Kv1.2 channels, increasing neuronal excitability and causing diabetic neuropathic pain symptoms; LAT1 inhibition alleviates these symptoms.\",\n      \"method\": \"RNA sequencing, label-free quantitative proteomics, patch clamp, immunostaining for membrane localization, LAT1 inhibitor treatment in mice\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics plus electrophysiology plus in vivo rescue, single lab, mechanism via LAT1 = Slc7a5 consistent with prior Slc7a5-Kv1.2 literature\",\n      \"pmids\": [\"38946582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A missense mutation I402T in the S6 segment of Kv1.2 (in Pingu mice) dramatically decreases the amount of functional Kv1 channels in cerebellar basket cell terminals without major changes in biophysical properties; this results in increased frequency and amplitude of spontaneous GABAergic IPSCs and reduced Purkinje cell firing, causing motor incoordination, which is partially rescued by acetazolamide or Kcna2 transgenic complementation.\",\n      \"method\": \"ENU mutagenesis screen, patch clamp in cerebellar slices, immunochemistry, CHO cell expression, transgenic complementation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mouse model with defined mutation plus electrophysiology in native tissue plus expression analysis plus transgenic rescue\",\n      \"pmids\": [\"20696761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"TsTX-Kα and α-dendrotoxin competitively block Kv1.2 K+ channels by binding to the same or closely related extracellular sites; TsTX-Kα blocks with Kd ~0.21 nM (10-fold more potent than DTX at 2.8 nM); TsTX-Kα does not affect kinetics or voltage dependence of activation; 4-AP blockade is unaffected by TsTX-Kα, indicating a distinct binding site for 4-AP.\",\n      \"method\": \"Whole-cell and patch-clamp recordings from B82 fibroblasts stably expressing Kv1.2, competitive binding analysis\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — competitive pharmacological dissection with multiple toxins in defined heterologous expression system\",\n      \"pmids\": [\"8355670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Kv1.2 downregulation in distal apical dendrites of CA3 pyramidal cells mediates mossy fiber-induced heterosynaptic LTP of perforant path (PP) EPSPs: Kv1.2 is polarized to distal apical dendrites; its downregulation specifically enhances PP-evoked EPSPs by facilitating activation of dendritic Na+ channels at distal dendrites; partial block of dendritic Na+ channels reverses the enhanced PP-EPSPs.\",\n      \"method\": \"Patch clamp, immunostaining for subcellular Kv1.2 distribution, compartmental simulations, TTX application in hippocampal slices\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology plus immunostaining plus computational modeling, single lab\",\n      \"pmids\": [\"26047212\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Kv1.2 (KCNA2) is a voltage-gated K+ channel whose crystal/cryo-EM structures establish that independent voltage-sensor domains couple to the pore via S4-S5 linker helices, gating charge is carried principally by the first S4 arginine, and toxins such as dendrotoxin and TsTX-Kα block the channel by occluding the extracellular pore mouth; channel function and surface expression are tuned by PKA-mediated phosphorylation at Ser-449, C-terminal cluster phosphorylation at Ser-440/441, N-linked glycosylation, and by dynamic interactions with cortactin (linking Kv1.2 to the actin cytoskeleton and endocytic machinery), RPTPα (reversing tyrosine kinase-mediated suppression), Kvβ subunits, Slc7a5, and sigma-1 receptor; in neurons Kv1.2 suppresses presynaptic hyperexcitability, regulates subthreshold excitability and state transitions, undergoes activity-dependent endocytosis from distal dendrites to enable intrinsic plasticity, and its expression is epigenetically silenced after nerve injury by DNMT3a, DNMT1, G9a, and MBD1-recruited methylation of the Kcna2 promoter, with transcription factor EBF1 directly activating Kcna2 transcription.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KCNA2 encodes Kv1.2, a voltage-gated potassium channel that sets neuronal excitability across somatic, axonal, presynaptic, and dendritic compartments, where it suppresses hyperexcitability and tunes state transitions [#1, #7, #26]. Atomic-resolution crystal and multi-state cryo-EM structures establish that independent voltage-sensor domains perform mechanical work on the pore through the S4-S5 linker, that gating charge (~10 e0) is carried principally by the first S4 arginine, and that pore-blocking toxins occlude the extracellular pore mouth — α-dendrotoxin inserting a lysine into the selectivity filter and displacing the outermost ion site [#0, #28, #30, #36]. Channel gating shows distinctive bimodal and use-dependent activation governed by the S2-S3 linker residue T252 and by cytoplasmic and extracellular redox-sensitive regulators [#20, #24, #25]. Surface expression and function are tuned by phosphorylation: PKA acts at Ser-449 and a C-terminal cluster (Ser-440/441) marks post-ER, surface channels and controls trafficking, while N-linked glycosylation promotes forward trafficking and stabilizes internalized channel [#6, #11, #29]. Kv1.2 activity is further set by a network of accessory and signaling partners — cortactin, which links the channel to actin and the endocytic machinery and is required for activity-dependent internalization; RPTPα, which opposes tyrosine-kinase-mediated current suppression downstream of muscarinic receptors; the amino acid transporter Slc7a5, which strongly hyperpolarizes activation and reduces channel protein; Kvβ subunits; and sigma-1 receptor [#4, #5, #3, #22, #31]. In neurons this regulation underlies intrinsic plasticity, as activity-dependent endocytosis of Kv1.2 from distal CA3 dendrites produces long-term potentiation of intrinsic excitability and heterosynaptic potentiation [#14, #37]. After peripheral nerve injury, Kcna2 is epigenetically silenced in DRG neurons through promoter methylation by DNMT3a, DNMT1, the histone methyltransferase G9a, MBD1-recruited DNMT3a, and an antisense lncRNA, while the transcription factor EBF1 directly activates Kcna2 transcription; loss of channel expression increases neuronal excitability and drives neuropathic pain [#17, #19, #18, #32, #27, #33]. De novo KCNA2 mutations cause epileptic encephalopathy through either dominant-negative loss-of-function or gain-of-function mechanisms [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing how peptide toxins block Kv1.2 provided the pharmacological tools needed to isolate Kv1.2-mediated currents in native tissue.\",\n      \"evidence\": \"Competitive binding and patch-clamp with TsTX-Kα and α-dendrotoxin on B82 cells stably expressing Kv1.2\",\n      \"pmids\": [\"8355670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of toxin occlusion\", \"Did not address channel function in vivo\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Mapping where Kv1.2 protein resides established that the channel occupies distinct neuronal compartments in a cell-type-specific manner, implying compartment-specific roles.\",\n      \"evidence\": \"Immunocytochemistry, in situ hybridization, and subcellular fractionation in mouse and rat brain\",\n      \"pmids\": [\"8046438\", \"8158277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of differential targeting unresolved\", \"Functional consequence of each localization not tested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identifying RPTPα as a Kv1.2-associated phosphatase explained how GPCR-driven tyrosine phosphorylation suppression of the channel is reversed.\",\n      \"evidence\": \"mAChR-dependent co-IP, in vitro binding, and Xenopus oocyte electrophysiology\",\n      \"pmids\": [\"9878055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific tyrosine residues targeted not fully defined here\", \"Endogenous neuronal relevance not directly shown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Discovery of a direct cortactin-Kv1.2 interaction linked the channel to the actin cytoskeleton and to phosphorylation-dependent regulation of current.\",\n      \"evidence\": \"Purified recombinant protein binding, reciprocal co-IP, mutagenesis, and electrophysiology in HEK293 cells\",\n      \"pmids\": [\"12151401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not yet define cortactin's role in trafficking versus current\", \"In vivo neuronal requirement not established\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Functional dissection in presynaptic terminals and striatal neurons established Kv1.2 as a suppressor of hyperexcitability and a regulator of subthreshold state transitions.\",\n      \"evidence\": \"Selective toxin pharmacology and paired/current-clamp recordings in calyx of Held and striatal slices\",\n      \"pmids\": [\"12777451\", \"13679409\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Heteromeric subunit composition only partially defined\", \"Upstream signals controlling channel availability not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The Kv1.2 crystal structure resolved the long-standing question of how voltage sensors mechanically couple to the pore.\",\n      \"evidence\": \"X-ray crystallography at 2.9 Å of the mammalian channel\",\n      \"pmids\": [\"16002579\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Captured a single (open) conformation\", \"Did not resolve inactivated or toxin-bound states\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of C-terminal phosphosites, gating-mode switches, and a glycosylation requirement showed that Kv1.2 surface expression and gating are post-translationally controlled.\",\n      \"evidence\": \"Tandem MS phosphosite mapping from brain, mutagenesis, surface assays, glycosidase treatment, and patch clamp including chimera/T252 analysis\",\n      \"pmids\": [\"18056633\", \"17324383\", \"17766348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinases and phosphatases for the C-terminal cluster not all identified\", \"Cytoplasmic regulator of slow gating mode unidentified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"cAMP/PKA signaling was shown to bidirectionally tune Kv1.2 surface levels through opposing trafficking pathways and endocytic machinery engaging cortactin.\",\n      \"evidence\": \"Surface biotinylation with PKA/endocytosis inhibitors and cortactin gene replacement with FRET and endocytosis assays\",\n      \"pmids\": [\"18003609\", \"17959782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of PKA-independent pathway not defined\", \"Link between specific phosphosites and endocytosis incomplete\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Pinpointing Ser-449 as the functionally critical PKA site connected PKA signaling directly to a defined molecular event on the channel.\",\n      \"evidence\": \"In vitro/in situ phosphorylation, MS, S449A mutagenesis, and patch clamp\",\n      \"pmids\": [\"19389710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Ser-449 acts through trafficking or gating in neurons not fully resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"A spontaneous S6 mutation in mice demonstrated that reduced functional Kv1.2 in basket cell terminals causes motor incoordination, linking channel availability to circuit output.\",\n      \"evidence\": \"ENU-derived Pingu mouse, cerebellar slice patch clamp, immunochemistry, and transgenic complementation\",\n      \"pmids\": [\"20696761\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which I402T reduces functional channel number unclear\", \"Human relevance not addressed at the time\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Activity-dependent Kv1.2 internalization was identified as a substrate for intrinsic plasticity, and sigma-1 receptor and D2 autoreceptor partnerships placed Kv1.2 in neuromodulatory signaling.\",\n      \"evidence\": \"Kv1.2 KO mice with endocytosis/PTK inhibitors and dendritic Ca2+ imaging; co-IP and electrophysiology for Sig-1R and D2-AR in striatal tissue\",\n      \"pmids\": [\"23981714\", \"23332758\", \"21233214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise endocytic adaptors recruiting Kv1.2 not fully defined\", \"Direct versus indirect nature of Sig-1R association left open\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery of a Kcna2 antisense lncRNA established transcriptional/RNA-level silencing as a driver of injury-induced Kv1.2 loss and neuropathic pain.\",\n      \"evidence\": \"MZF1 promoter binding assays, expression manipulation, patch clamp, and behavioral pain assays in DRG\",\n      \"pmids\": [\"23792947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab characterization\", \"Relationship to DNA-methylation silencing not integrated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linking de novo KCNA2 mutations to epileptic encephalopathy via two opposite biophysical mechanisms established the channel as a Mendelian disease gene.\",\n      \"evidence\": \"Next-generation sequencing and two-electrode voltage-clamp functional characterization of mutant channels\",\n      \"pmids\": [\"25751627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype determinants beyond gain/loss dichotomy incomplete\", \"In vivo consequences in neurons not directly modeled here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Use-dependent activation and dendritic Kv1.2 downregulation were shown to confer unique gating behavior and to mediate heterosynaptic potentiation, refining Kv1.2's role in dendritic computation.\",\n      \"evidence\": \"Patch clamp in HEK and hippocampal neurons; immunostaining, compartmental modeling, and TTX in slices\",\n      \"pmids\": [\"25716850\", \"26047212\", \"25779871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of use-dependent activation not fully resolved\", \"Single-lab dendritic studies\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"DNA methyltransferases and histone methyltransferase G9a were identified as effectors silencing Kcna2 after nerve injury, defining an epigenetic axis driving neuropathic pain.\",\n      \"evidence\": \"Methylation assays, reporter assays, siRNA/AAV manipulation, patch clamp, and behavioral assays in DRG (DNMT3a, DNMT1, G9a)\",\n      \"pmids\": [\"28270689\", \"31182635\", \"27874088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among DNMT3a, DNMT1, and G9a not fully ordered\", \"Some studies single-lab and Medium confidence\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of Slc7a5 as a Kv1.2 complex partner revealed a powerful gating and protein-level regulator with direct relevance to epilepsy mutants.\",\n      \"evidence\": \"MS interactome, patch clamp, western blot, and co-expression with wild-type and disease-mutant channels (and Slc3a2)\",\n      \"pmids\": [\"30356053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the Kv1.2-Slc7a5 interaction unknown\", \"Endogenous neuronal stoichiometry not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"MBD1 was shown to recruit DNMT3a to the Kcna2 promoter, providing the reader/effector link in injury-induced epigenetic silencing.\",\n      \"evidence\": \"ChIP for DNMT3a recruitment, MBD1 KO mice, AAV overexpression, and pain behavior\",\n      \"pmids\": [\"30266739\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Direct effect on channel protein not measured\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating sigma-1 receptor modulation of bimodal Kv1.2 gating, including an ALS16 mutation that abolishes it, connected channel gating to a disease-relevant receptor.\",\n      \"evidence\": \"Patch clamp, co-transfection, Sig-1R ligands, and the E102Q dominant-negative mutation in HEK293 cells\",\n      \"pmids\": [\"31222975\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding not demonstrated\", \"Single-lab heterologous system\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing convergent regulation of Kv1.2 by Slc7a5 and Kvβ1.2 clarified how accessory subunits jointly shape availability and inactivation.\",\n      \"evidence\": \"Whole-cell patch clamp and western blot with co-transfected subunit combinations in HEK cells\",\n      \"pmids\": [\"32311044\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab\", \"Native neuronal relevance of triple-partner regulation untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying EBF1 as a direct activator of Kcna2 transcription provided the positive regulatory counterpart to injury-induced silencing.\",\n      \"evidence\": \"ChIP, luciferase reporter, AAV overexpression/knockdown, and pain behavior in DRG\",\n      \"pmids\": [\"37607607\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab\", \"Interplay with repressive epigenetic machinery not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linking BCAA deficiency to ATF4-driven LAT1/Slc7a5 upregulation extended Slc7a5-mediated Kv1.2 suppression to diabetic neuropathic pain in vivo.\",\n      \"evidence\": \"RNA-seq, quantitative proteomics, patch clamp, membrane-localization imaging, and LAT1 inhibitor treatment in mice\",\n      \"pmids\": [\"38946582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab\", \"Whether effect is purely via Slc7a5 not fully isolated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multi-state cryo-EM structures resolved how Kv1.2 inactivates, conducts ions, and is blocked by dendrotoxin at atomic detail.\",\n      \"evidence\": \"Cryo-EM in open, C-type inactivated, dendrotoxin-blocked, and Na+-bound states\",\n      \"pmids\": [\"39945513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"C-type inactivated W366F state only low-resolution\", \"Structures of accessory-partner complexes not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many post-translational, accessory-protein, and transcriptional regulators of Kv1.2 are integrated in a single compartmentalized neuron, and the structural basis of partner interactions, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of Kv1.2 with Slc7a5, cortactin, or sigma-1 receptor\", \"Integration of competing trafficking/silencing pathways in vivo not established\", \"Mechanism of redox- and cytoplasm-dependent gating-mode switching unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 7, 26, 28, 30]},\n      {\"term_id\": \"GO:0005216\", \"supporting_discovery_ids\": [0, 7, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 6, 12, 29, 34]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6, 9, 29]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [7, 14, 26, 37]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 12, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 17, 27, 35]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [6, 10, 29]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KCNA1\", \"KCNA5\", \"CTTN\", \"PTPRA\", \"SLC7A5\", \"KCNAB2\", \"SIGMAR1\", \"DRD2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}