{"gene":"KCNA5","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1995,"finding":"Kv1.5 protein localizes to intercalated disk regions in human atrial and ventricular myocytes, as determined by co-localization with connexin and N-cadherin antibodies; NH2-terminal antibodies additionally stained vascular smooth muscle, suggesting differential epitope accessibility between cardiac and vascular myocytes.","method":"Immunofluorescence with two distinct anti-channel antibodies, co-localization with connexin and N-cadherin markers","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment in human cardiac tissue with two antibodies and co-localization controls, single lab","pmids":["7615797"],"is_preprint":false},{"year":1996,"finding":"The Kvβ2.1 subunit co-assembles with hKv1.5 alpha subunit, shifting the midpoints for activation (~14 mV negative) and inactivation (~12 mV negative) and increasing the extent of slow inactivation, thereby altering Kv1.5 gating kinetics.","method":"Molecular cloning, immunopurification, Western blot, whole-cell patch-clamp in HEK293 and L-cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in multiple cell lines, molecular cloning, and functional electrophysiology with multiple orthogonal methods in one study","pmids":["8576199"],"is_preprint":false},{"year":1997,"finding":"Kv1.5 protein expression is reduced by >50% in both left and right atrial appendages of patients with chronic atrial fibrillation, in parallel with a reduction in sustained (IKsus/IKur) outward K+ current density, consistent with Kv1.5 underlying IKur.","method":"Quantitative Western blot, nystatin-perforated patch-clamp recordings of atrial myocytes","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (Western blot + patch-clamp) in human tissue, single lab","pmids":["9168779"],"is_preprint":false},{"year":1998,"finding":"Co-expression of human Kvβ3.1 with Kv1.5 in Chinese hamster ovary cells produces a novel fast-inactivating (A-type) outward current, demonstrating that Kvβ3.1 confers rapid inactivation on Kv1.5.","method":"Heterologous co-expression in CHO cells, whole-cell patch-clamp","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution with electrophysiology, single lab","pmids":["9857044"],"is_preprint":false},{"year":1999,"finding":"PKA phosphorylation of serine-24 on the Kvβ1.3 NH2-terminus reduces Kvβ1.3-induced fast inactivation of Kv1.5; substitution of serine-24 with a negatively charged residue mimics phosphorylation (reduces inactivation) while a positively charged residue enhances inactivation.","method":"Site-directed mutagenesis of Kvβ1.3 serine-24, patch-clamp in Xenopus oocytes and HEK293 cells, PKA activation/inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis with charge-swap validation, two heterologous expression systems, multiple orthogonal experiments in one study","pmids":["10318802"],"is_preprint":false},{"year":1999,"finding":"Slow inactivation of hKv1.5 is regulated by intracellular ion occupancy: intracellular K+ (or Cs+) concentration modulates inactivation with low affinity (Kd ~34–43 mM), and this is more potent than extracellular ion effects; the inactivation mechanism is not classical C-type but is closely coupled to ion permeation through the pore.","method":"Whole-cell patch-clamp with varied intra- and extracellular cation concentrations, including symmetric reduction experiments and gating current analysis","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biophysical assay with multiple ion conditions, single lab","pmids":["10050000"],"is_preprint":false},{"year":2000,"finding":"Kv1.5 is associated with Src family protein tyrosine kinases in astrocytes (demonstrated by co-immunoprecipitation); Src-mediated tyrosine phosphorylation of Kv1.5 is required for full channel activity and astrocyte proliferation, and this phosphorylation is downregulated during differentiation.","method":"Co-immunoprecipitation, antisense oligodeoxynucleotides, Src-specific inhibitor PP2, constitutively active Src transfection, whole-cell patch-clamp","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional electrophysiology and genetic manipulation, single lab","pmids":["10884308"],"is_preprint":false},{"year":2001,"finding":"Alpha-actinin-2 binds to a discrete region (amino acids 73–148) of the Kv1.5 N-terminus via its internal spectrin repeats, as demonstrated by yeast two-hybrid and in vitro binding assays; this interaction does not occur with Kv1.1, Kv1.2, or Kv1.3 N-termini.","method":"Yeast two-hybrid analysis, in vitro binding assays, deletion analysis","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal binding methods with domain deletion mapping, single lab","pmids":["11389904"],"is_preprint":false},{"year":2001,"finding":"SAP97 co-localizes and co-immunoprecipitates with Kv1.5 in cardiac myocytes at intercalated disks and lateral membranes; the C-terminal PDZ-binding motif (TDL) of Kv1.5 is required for this interaction, and SAP97 co-expression augments Kv1.5 currents in Xenopus oocytes.","method":"Co-immunoprecipitation, immunocytochemistry, site-directed mutagenesis (TDL→AAA), functional expression in Xenopus oocytes","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and mutagenesis in multiple systems, single lab","pmids":["11709425"],"is_preprint":false},{"year":2001,"finding":"Heteromultimeric Kv1.2/Kv1.5 channels underlie the 4-AP-sensitive delayed rectifier K+ current in rabbit portal vein vascular myocytes; tandem-coupled [Kv1.5/Kv1.2]2 heterotetramers reproduced the characteristic voltage-dependent shift in activation seen in native channels but absent in Kv1.5 homotetramers.","method":"Patch-clamp of native vascular myocytes, heterologous expression of homo- and heterotetramers (including tandem constructs) in mammalian cells, pharmacological characterization","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tandem construct and functional pharmacology, single lab","pmids":["11717161"],"is_preprint":false},{"year":2002,"finding":"External H+ and Zn2+ inhibit hKv1.5 by stabilizing an inactivated state; this inhibition requires histidine H463 (in the channel turret) and R487 (near the outer pore mouth), and is relieved by extracellular K+ through a non-competitive mechanism.","method":"Site-directed mutagenesis (H463Q, R487V), whole-cell patch-clamp, gating current analysis in non-conducting mutant hKv1.5 W472F, varied extracellular [K+]","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of multiple residues combined with gating current analysis and ionic substitution in a single rigorous study","pmids":["12015417"],"is_preprint":false},{"year":2002,"finding":"PKA activity is required to maintain Kv1.5 current levels; inhibition of PKA reduces Kv1.5 currents by revealing endogenous phosphatase activity, and this regulation requires an intact actin cytoskeleton and alpha-actinin-2 (antisense knockdown of alpha-actinin-2 abolishes the effect).","method":"Xenopus oocyte expression, PKA activators/inhibitors, cytochalasin (actin disruption), phalloidin, antisense oligonucleotides against alpha-actinin-2, alkaline phosphatase injection, orthovanadate","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological interventions and antisense KD in single lab","pmids":["11809852"],"is_preprint":false},{"year":2002,"finding":"PKC activation (via PMA) markedly reduces Kv1.5 current only when Kv1.5 is co-expressed with Kvβ1.2 (but not Kvβ1.3); all three proteins (Kv1.5, Kvβ1.2, Kvβ1.3) are substrates for PKC phosphorylation, and Kv1.5 assembles in vivo with both beta subunits.","method":"Co-expression in HEK293 cells, whole-cell patch-clamp, phorbol ester activation, PKC inhibitors, in vivo assembly demonstrated","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology with pharmacological controls and subunit co-assembly evidence, single lab","pmids":["12130714"],"is_preprint":false},{"year":2003,"finding":"Kv1.5 is the molecular basis of IKur in canine atrial myocytes; a Kv1.5-selective compound (not affecting Kv3.1, hERG, or sodium channels) fully suppressed IKur tail currents and prolonged atrial action potentials, while Kv3.1 protein was undetectable in atrial membrane fractions.","method":"RT-PCR, Western blot of cytosolic and membrane fractions, confocal immunostaining, voltage-clamp, action potential recordings in isolated canine atrial myocytes","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (molecular + functional + pharmacological) replicated across modalities in one study","pmids":["14500335"],"is_preprint":false},{"year":2003,"finding":"Different SAP97 isoforms differentially regulate Kv1.5: the cardiac isoform lacking I1A insert increases Kv1.5 current (215%) and promotes surface membrane clustering, while the isoform containing I1A abolishes this effect; both isoforms co-immunoprecipitate with Kv1.5.","method":"RT-PCR isoform cloning, co-immunoprecipitation, confocal imaging of GFP-tagged channels, patch-clamp in CHO cells, W623F SH3-domain mutation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, mutagenesis, imaging, and functional electrophysiology, single lab","pmids":["12970345"],"is_preprint":false},{"year":2003,"finding":"SAP97 increases hKv1.5 current through an indirect mechanism dependent on the Kv1.5 N-terminus (not the C-terminal PDZ-binding motif); no physical interaction between SAP97 and Kv1.5 could be detected by co-IP, co-localization, or yeast two-hybrid in most experiments.","method":"Deletion mutagenesis of Kv1.5 N- and C-termini, yeast two-hybrid, co-IP from HEK cells and rat ventricular myocytes, co-localization in cardiac myocytes, Xenopus oocyte functional expression","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus multiple interaction assays, single lab; notably, physical interaction was largely negative","pmids":["12860415"],"is_preprint":false},{"year":2005,"finding":"Kv1.5 surface expression is regulated by retrograde trafficking via the dynein motor complex: disruption of dynein-dynactin (by p50/dynamitin overexpression), inhibition of endocytosis (dynamin inhibitory peptide), or microtubule depolymerization (nocodazole) all increase Kv1.5 current density and redistribute channels to the plasma membrane; Kv1.5 co-immunoprecipitates with the dynein motor complex in an interaction requiring the N-terminal SH3-binding domain.","method":"Overexpression of p50/dynamitin, dynamin inhibitory peptide, nocodazole, Proteinase K surface accessibility assay, co-immunoprecipitation, confocal imaging in HEK cells and rat atrial myocytes, patch-clamp","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional and biochemical methods in two cell systems, with domain-mapping of the interaction","pmids":["16051887"],"is_preprint":false},{"year":2006,"finding":"Kv1.5 is internalized upon activation of 5-HT2A receptors by serotonin via a pathway involving phospholipase C, protein kinase C, tyrosine kinases, and caveolae-mediated endocytosis; 5-HT2A receptors and caveolin-1 co-immunoprecipitate with Kv1.5 channels in pulmonary artery homogenates.","method":"Co-immunoprecipitation, pharmacological inhibitors (ketanserin, U73122, Gö6976, genistein, tyrphostin 23, beta-cyclodextrin, concanavalin A), patch-clamp, confocal imaging of channel internalization in rat PASMC and Ltk- cells stably expressing hKv1.5","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus pharmacological dissection and functional electrophysiology, single lab","pmids":["16527989"],"is_preprint":false},{"year":2006,"finding":"Kv1.5 and Kv1.3 form functional heterotetramers in macrophages; co-expression of Kv1.5 positively shifts K+ current half-activation voltage, both subunits co-immunoprecipitate and co-localize at the membrane, and FRET studies confirm heterotetrameric assembly; TNF-α activation increases Kv1.3 without changing Kv1.5, altering the pharmacological profile.","method":"Co-immunoprecipitation, co-localization by microscopy, FRET, Xenopus oocyte co-expression with varied subunit ratios, HEK293 co-expression, electrophysiology, pharmacology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — FRET plus co-IP plus functional reconstitution in multiple systems, multiple orthogonal methods","pmids":["17038323"],"is_preprint":false},{"year":2006,"finding":"A nonsense mutation (E375X) in KCNA5 truncates Kv1.5 at the S4-S6 voltage sensor, pore, and C-terminus; heterologously expressed E375X fails to generate IKur and exerts a dominant-negative effect on wild-type current, leading to action potential prolongation and early afterdepolarizations in human atrial myocytes. Aminoglycoside-induced translational read-through of the premature stop codon rescues channel function.","method":"Genomic DNA scanning, heterologous expression, whole-cell patch-clamp, action potential recordings in human atrial myocytes, murine in vivo model, aminoglycoside read-through rescue","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutation characterization with functional reconstitution, dominant-negative assessment, native cell AP recordings, and pharmacological rescue in one study","pmids":["16772329"],"is_preprint":false},{"year":2006,"finding":"AVE0118 blocks Kv1.5 by binding to the inner cavity of the channel pore; alanine-scanning mutagenesis identified Thr479, Thr480, Val505, Ile508, Val512, and Val516 (facing the central cavity) and Ile502 and Leu510 (facing away from cavity) as key binding residues; block is open-state preferring and slows current deactivation ('foot-in-the-door' mechanism).","method":"Alanine-scanning mutagenesis of the pore domain, two-microelectrode voltage-clamp in Xenopus oocytes, homology model docking","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic alanine-scanning mutagenesis combined with functional electrophysiology and structural docking in a single study","pmids":["16835355"],"is_preprint":false},{"year":2007,"finding":"Kv1.5 is post-translationally modified by SUMO-1, -2, and -3 at two membrane-proximal cytoplasmic SUMO consensus sites; Kv1.5 interacts specifically with the SUMO-conjugating enzyme Ubc9 and serves as a substrate in a minimal in vitro reconstituted SUMOylation reaction; disruption of SUMOylation sites or expression of SUMO protease SENP2 causes a ~15 mV hyperpolarizing shift in the voltage dependence of steady-state inactivation.","method":"In vitro reconstituted SUMOylation assay, in vivo SUMOylation with SUMO-specific protease deconjugation (SENP2, Ulp1), mutagenesis of SUMO target motifs, whole-cell patch-clamp","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution plus mutagenesis plus functional electrophysiology, multiple orthogonal methods in one study","pmids":["17261810"],"is_preprint":false},{"year":2007,"finding":"Rab4- and Rab11-dependent endosomal recycling pathways regulate steady-state Kv1.5 surface levels in atrial myocytes: Kv1.5 internalizes to EEA1-positive early endosomes and recycles back to the plasma membrane; dominant-negative Rab4S22N and Rab11S25N decrease surface Kv1.5 levels while GTPase-deficient Rab4Q67L and Rab11Q70L increase them; Rab11 co-immunoprecipitates with Kv1.5.","method":"Kinetic internalization assays, co-localization with endosomal markers, co-immunoprecipitation, dominant-negative and constitutively active Rab GTPase mutants, live-cell surface labeling, electrophysiology in HL-1 mouse atrial myocytes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple Rab mutants with reciprocal functional effects, co-IP, and kinetic studies in atrial myocytes","pmids":["17673464"],"is_preprint":false},{"year":2007,"finding":"S-acylation (palmitoylation) of Kv1.5 on COOH-terminal cysteines via hydroxylamine-sensitive thioester bonds is required for normal surface expression; pharmacological inhibition of S-acylation decreases surface Kv1.5 and targets it for proteasomal degradation; S-acylation occurs in the biosynthetic pathway of nascent channel protein.","method":"Hydroxylamine treatment, inhibitors of S-acylation, proteasome inhibitors, COOH-terminal cysteine mutation, confocal microscopy, Western blot in transfected fibroblasts","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical demonstration of thioester bond, mutagenesis of cysteines, and functional consequence in single lab","pmids":["17344312"],"is_preprint":false},{"year":2007,"finding":"Caveolin is required for trafficking of Kv1.5 to cholesterol-rich lipid raft microdomains; in cells lacking endogenous caveolin, Kv1.5 association with low-density detergent-resistant membranes requires exogenous caveolin co-expression; caveolin-trafficking mutants sequester Kv1.5 in intracellular compartments, reducing surface channel expression; caveolin co-expression induces depolarizing shifts in Kv1.5 activation and inactivation analogous to elevated cholesterol effects.","method":"Sucrose gradient fractionation, co-expression with caveolin and caveolin trafficking mutants, whole-cell patch-clamp, confocal microscopy","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical and functional approaches, single lab","pmids":["18045854"],"is_preprint":false},{"year":2007,"finding":"Membrane cholesterol depletion (via methyl-β-cyclodextrin) causes redistribution of Kv1.5 subunits from cholesterol-enriched microdomains into larger clusters throughout the plasma membrane, increasing IKur current; Kv1.5 subunits are concentrated in cholesterol-rich microdomains distinct from caveolae in rat atrial cardiomyocytes.","method":"Methyl-β-cyclodextrin treatment, GFP-tagged Kv1.5 imaging in live neonatal cardiomyocytes, sucrose gradient fractionation, patch-clamp in rat atrial myocytes, cholesterol loading with LDL","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging with functional electrophysiology, single lab","pmids":["17525113"],"is_preprint":false},{"year":2008,"finding":"SAP97 retains and immobilizes Kv1.5 subunits in the plasma membrane of cardiac myocytes, increasing IKur current density and reducing channel mobility (FRAP); SAP97 overexpression clusters endogenous Kv1.5 at myocyte-myocyte contacts.","method":"Adenovirus-mediated SAP97 overexpression in rat neonatal cardiomyocytes and CHO cells, FRAP, immunocytochemistry, whole-cell patch-clamp, cell-attached patch recordings","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRAP plus functional electrophysiology plus imaging, single lab","pmids":["18245566"],"is_preprint":false},{"year":2008,"finding":"After internalization, Kv1.5 rapidly associates with Rab5- and Rab4-positive early endosomes (fast recycling pathway), and a fraction is targeted to Rab7-positive late endosomes for degradation; Rab5DN increases Kv1.5 current ~2-fold, Rab4DN similarly increases currents, Rab7 overexpression decreases currents in H9c2 myoblasts; Rab11-positive perinuclear recycling is slow and only evident after 24 h.","method":"Dominant-negative and constitutively active Rab GTPase mutants, post-internalization trafficking assays, co-localization with endosomal markers, whole-cell patch-clamp in H9c2 myoblasts and HEK293 cells","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple Rab mutants with reciprocal effects, co-localization studies, single lab","pmids":["18755741"],"is_preprint":false},{"year":2008,"finding":"The C-terminal domain of Kv1.5 (specifically Arg543-Val583) interacts with Kvβ subunits in a pyridine-nucleotide-dependent manner: NADPH accelerates Kvβ3-induced inactivation while NADP+ reverses it; deletion of the C-terminus abolishes nucleotide-sensitive Kvβ regulation; a GST-C-terminal fusion protein binds Kvβ2:NADPH with higher affinity than Kvβ2:NADP+.","method":"C-terminal deletion mutagenesis, GST pull-down with brain lysates, patch-clamp with intrapipette nucleotide infusion, co-expression in COS-7 cells","journal":"Pflugers Archiv","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — GST pull-down plus mutagenesis plus functional electrophysiology, single lab","pmids":["22426702"],"is_preprint":false},{"year":2008,"finding":"Four-and-a-half LIM protein 1 (FHL1) physically interacts with the Kv1.5/KCNA5 C-terminal domain in human atrium; co-expression of FHL1 markedly increases Kv1.5 current density and shifts activation to more positive potentials, and increases the extent and rate of slow inactivation.","method":"GST-KCNA5 C-terminal pull-down with mass spectrometry, co-immunoprecipitation from human atrium and CHO cells, confocal microscopy, patch-clamp in CHO cells","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — GST pull-down with MS identification, co-IP in native tissue, and functional reconstitution, multiple orthogonal methods","pmids":["18281375"],"is_preprint":false},{"year":2008,"finding":"Kv1.3 association modifies Kv1.5 trafficking: Kv1.3/Kv1.5 heterotetramers (confirmed by FRET) target to distinct surface microdomains with higher lateral mobility than Kv1.3 homotetramers; immunoprecipitation shows heteromeric channels associate with caveolar raft domains differently from Kv1.3 homomers; FRAP reveals higher mobility for hybrid channels.","method":"FRET, FRAP, co-immunoprecipitation, cholesterol depletion, caveolae co-localization, pharmacology in HEK cells and LPS-activated macrophages","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET and FRAP plus co-IP, multiple orthogonal methods, single lab","pmids":["18218624"],"is_preprint":false},{"year":2009,"finding":"Cholesterol regulates Kv1.5 surface expression by modulating trafficking through the Rab11-associated recycling endosome: cholesterol depletion promotes exocytosis of Kv1.5 from a Rab11-positive intracellular pool; dominant-negative Rab11 (but not Rab4) prevents the cholesterol depletion-induced increase in IKur; Rab11 co-immunoprecipitates with hKv1.5-EGFP.","method":"Whole-cell patch-clamp, single-channel recordings, FRAP, 3D microscopy, co-immunoprecipitation, dominant-negative Rab11 and Rab4 mutants, NEM and GTP-γ-S inhibitors in rat adult atrial myocytes","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, dominant negatives, single-channel, FRAP) in native atrial myocytes","pmids":["19706553"],"is_preprint":false},{"year":2010,"finding":"A novel 33-bp coding region deletion in the Kv1.5 N-terminus (removing 11 amino acids including an SH3-domain binding site for Src-family tyrosine kinases) causes ~60% reduction in IKur and a dominant-negative effect; pretreatment with Src inhibitor PP2 prevents v-Src from suppressing wild-type current, whereas the mutant channel is unresponsive to v-Src, implicating tyrosine kinase signaling through the N-terminal SH3-binding domain in Kv1.5 regulation.","method":"Site-directed mutagenesis, transfection in cells, whole-cell patch-clamp, Src inhibitor PP2, v-Src kinase treatment","journal":"Heart rhythm","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional electrophysiology with pharmacological Src inhibition and mutant characterization, single lab","pmids":["20638934"],"is_preprint":false},{"year":2012,"finding":"Oxidative stress leads to sulfenic acid modification of Kv1.5 on a single C-terminal cysteine (C581); this modification is necessary and sufficient to reduce channel surface expression, promote internalization, and block recycling; under prolonged oxidative stress, sulfenic acid modification triggers channel degradation. Sulfenic acid-modified proteins including Kv1.5 are elevated in human atrial fibrillation.","method":"Sulfenic acid-specific probe (DAz) labeling with Western blot, site-directed mutagenesis of C581, live-cell immunofluorescence, whole-cell voltage-clamp, Western blot in human AF tissue","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — chemical probe labeling, cysteine mutagenesis, and functional trafficking assays with human disease tissue validation","pmids":["22843785"],"is_preprint":false},{"year":2012,"finding":"AMPK activation (wild-type and constitutively active γR70Q, but not inactive αK45R mutant) significantly reduces Kv1.5-mediated K+ currents and decreases Kv1.5 protein abundance in the cell membrane; Nedd4-2 co-expression similarly downregulates Kv1.5 currents, suggesting AMPK acts in part via Nedd4-2.","method":"Xenopus oocyte injection with Kv1.5 ± AMPK constructs, two-electrode voltage-clamp, chemiluminescence and confocal microscopy for membrane protein abundance","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional electrophysiology with AMPK mutant panel and Nedd4-2 co-expression, single lab","pmids":["23221389"],"is_preprint":false},{"year":2012,"finding":"PKC activity is required for Kvβ1.3-induced fast inactivation of Kv1.5; PKC inhibition (calphostin C or siRNA knockdown of all PKC isoforms) abolishes fast inactivation without dissociating Kv1.5 from Kvβ1.3 (co-IP and co-localization preserved); a Kv1.5 channelosome comprising Kv1.5, Kvβ1.3, RACK1, PKCβI, PKCβII, and PKCθ was identified by co-immunoprecipitation in HEK293 cells and rat ventricular tissue.","method":"Co-immunoprecipitation, immunocytochemistry, siRNA knockdown of PKC isoforms, calphostin C inhibition, whole-cell patch-clamp, rat ventricular and atrial tissue","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP in native tissue, siRNA knockdown, pharmacological inhibition, and electrophysiology, multiple orthogonal methods","pmids":["22547057"],"is_preprint":false},{"year":2012,"finding":"Novel gain-of-function (E48G, A305T, D322H) and loss-of-function (Y155C, D469E, P488S) mutations in KCNA5 were identified in patients with early-onset lone atrial fibrillation; loss-of-function mutants showed decreased surface expression by confocal microscopy, while gain-of-function mutants showed preserved surface expression with increased IKur.","method":"Sequencing of KCNA5, confocal microscopy for surface expression, whole-cell patch-clamp in transfected cells","journal":"European heart journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional characterization of multiple mutations with imaging and electrophysiology, single lab","pmids":["23264583"],"is_preprint":false},{"year":2015,"finding":"Kv1.5 channels in vascular smooth muscle are required for coronary metabolic dilation: Kv1.5-null mice show impaired myocardial blood flow and tissue oxygen tension during cardiac stress despite elevated cardiac work; smooth muscle-specific re-expression of Kv1.5 in the null background rescues metabolic dilation; isolated arteries from Kv1.5-null mice show impaired relaxation to H2O2 but normal responses to adenosine and acetylcholine.","method":"Kv1.5 knockout mice, inducible smooth muscle-specific Kv1.5 rescue transgene, in vivo hemodynamic and blood flow measurements (micromanometer catheters), myocardial tissue oxygen tension, isolated artery vasoreactivity studies","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with rescue by smooth muscle-specific re-expression, in vivo and ex vivo functional measurements","pmids":["26224794"],"is_preprint":false},{"year":2015,"finding":"Urate taken up intracellularly via URATv1 increases Kv1.5 protein expression and IKur in HL-1 atrial myocytes through NADPH oxidase-derived reactive oxygen species and ERK phosphorylation; the ERK inhibitor PD98059 and antioxidants (NAC, apocynin) abolish the urate-induced increase in Kv1.5.","method":"URATv1 inhibitor (benzbromarone), ABCG2 inhibitor (KO143), N-acetylcysteine, apocynin, ERK inhibitor PD98059, ROS flow cytometry, RT-PCR, immunoblot, patch-clamp in HL-1 cells","journal":"Circulation journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with multiple inhibitors and functional electrophysiology, single lab","pmids":["26477273"],"is_preprint":false},{"year":2015,"finding":"DNA methylation of the KCNA5 promoter epigenetically silences Kv1.5 channel expression in Ewing sarcoma cells; treatment with the DNA methylation inhibitor decitabine restores Kv1.5 expression and inhibits Ewing sarcoma cell proliferation.","method":"Promoter methylation analysis, decitabine treatment, Kv1.5 expression assays, cell proliferation assays","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — methylation-restoration with functional proliferation readout, single lab","pmids":["26573141"],"is_preprint":false},{"year":2005,"finding":"Kv1.5 is degraded by the proteasome: proteasome inhibitors (MG132, ALLN, lactacystine) prolong Kv1.5 half-life (~6.7 h), increase ubiquitinated Kv1.5 levels, and increase IKur by stabilizing channel protein in the ER/Golgi; lysosomal inhibition has no effect; this degradation pathway was also demonstrated in endogenous Kv1.5 in rat atrial cells.","method":"Pulse-chase analysis, proteasome and lysosomal inhibitors, immunofluorescence, patch-clamp, brefeldin A and colchicine treatment in COS cells and rat atrial cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulse-chase plus pharmacological inhibitors plus functional electrophysiology in two cell systems, single lab","pmids":["16185660"],"is_preprint":false},{"year":2006,"finding":"Kv1.5 does not localize to caveolae in rat and canine cardiac myocytes: co-immunoprecipitation of Kv1.5 with caveolin-3 was not detected (though caveolin-3/eNOS and caveolin-3/β-dystroglycan interactions were), and wide-field/deconvolution microscopy showed <12% co-localization of Kv1.5 with caveolin-3 in atrial myocytes; in HEK293 cells Kv1.5 does not partition into low-buoyancy raft fractions.","method":"Co-immunoprecipitation, wide-field microscopy with deconvolution, immunoelectron microscopy, sucrose gradient fractionation in rat and canine cardiac tissue and HEK293 cells","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple negative co-localization/co-IP methods with positive controls, single lab; notable negative finding for caveolae association","pmids":["17054951"],"is_preprint":false},{"year":1993,"finding":"Dexamethasone (glucocorticoid) rapidly induces Kv1.5 gene transcription in GH3 pituitary cells, increasing Kv1.5 mRNA and ~3-fold increasing Kv1.5 protein (76 kDa, t1/2 ~4 hr) within 12 h, which is associated with increased noninactivating voltage-gated K+ current; Kv1.5 mRNA turnover (t1/2 ~0.5 hr) is not affected.","method":"Nuclear run-on transcription assay, mRNA stability assay, immunoblot, whole-cell patch-clamp in GH3 cells","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcription run-on plus protein quantification plus functional electrophysiology, single lab","pmids":["8352944"],"is_preprint":false}],"current_model":"Kv1.5 (KCNA5) is a voltage-gated K+ channel alpha-subunit that underlies the ultrarapid delayed rectifier current IKur in human atrial myocytes and regulates membrane potential in vascular smooth muscle; its function and surface expression are governed by a multi-layered regulatory network including: co-assembly with Kvβ subunits (Kvβ1.2, Kvβ1.3, Kvβ2.1, Kvβ3.1) that modulate inactivation kinetics; phosphorylation by PKA (via Kvβ1.3 Ser24), PKC (requiring Kvβ1.2 co-expression), and Src-family tyrosine kinases (via N-terminal SH3-binding domain); post-translational modifications by SUMOylation (shifting inactivation voltage dependence) and S-acylation (required for biosynthetic trafficking); redox-sensitive sulfenic acid modification of C-terminal C581 (triggering internalization and degradation under oxidative stress); and dynamic trafficking through Rab5/Rab4-mediated endocytosis, Rab4/Rab11-dependent recycling, and dynein-dependent retrograde transport along microtubules, with cholesterol-dependent recruitment from Rab11-positive recycling endosomes; anchoring proteins including SAP97 (via indirect N-terminal mechanism), FHL1 (C-terminal interaction increasing current and altering gating), and alpha-actinin-2 (N-terminal interaction) regulate surface expression and localization; Kv1.5 forms heterotetramers with Kv1.3 in macrophages and Kv1.2 in vascular smooth muscle, altering biophysical and pharmacological properties; loss-of-function mutations cause atrial fibrillation through action potential prolongation, while the channel is also essential for H2O2-sensitive coronary metabolic dilation in vascular smooth muscle."},"narrative":{"mechanistic_narrative":"KCNA5 encodes Kv1.5, a voltage-gated K+ channel alpha-subunit that underlies the ultrarapid delayed rectifier current IKur in atrial myocytes and controls membrane potential in vascular smooth muscle [PMID:9168779, PMID:14500335, PMID:26224794]. In the heart it localizes to intercalated disk regions and lateral membranes [PMID:7615797, PMID:11709425], where it forms the molecular basis of atrial IKur and shapes the atrial action potential [PMID:14500335]. Channel gating and inactivation are extensively tuned by co-assembled Kvβ subunits — Kvβ2.1 shifts activation and inactivation voltage dependence and enhances slow inactivation [PMID:8576199], Kvβ3.1 confers fast A-type inactivation [PMID:9857044], and Kvβ regulation is read out through the channel C-terminus in a pyridine-nucleotide (NADPH/NADP+)-dependent manner [PMID:22426702]. This Kvβ-conferred inactivation is itself a signaling node: PKA phosphorylation of Kvβ1.3 Ser24 reduces fast inactivation [PMID:10318802], while PKC activity is required for Kvβ1.3-induced fast inactivation within a defined Kv1.5/Kvβ1.3/RACK1/PKC channelosome [PMID:12130714, PMID:22547057]. Surface density is set by a multilayered trafficking and modification network: S-acylation of C-terminal cysteines is needed for biosynthetic delivery [PMID:17344312], SUMOylation at membrane-proximal sites shifts inactivation voltage dependence [PMID:17261810], and the channel is internalized through Rab5/Rab4 early endosomes and recycled via Rab4/Rab11 pathways, with dynein-dependent retrograde transport along microtubules and cholesterol-sensitive recruitment from Rab11-positive recycling endosomes opposing surface expression [PMID:16051887, PMID:17673464, PMID:18755741, PMID:19706553]. Oxidative stress drives sulfenic acid modification of C-terminal Cys581, which promotes internalization, blocks recycling, and targets the channel for degradation, a modification elevated in human atrial fibrillation [PMID:22843785]. Anchoring partners FHL1 (C-terminal) and alpha-actinin-2 (N-terminal) increase current and modulate gating and localization [PMID:11389904, PMID:18281375], and SAP97 increases IKur and clusters/immobilizes channels at cell-cell contacts [PMID:11709425, PMID:12970345, PMID:18245566]. Kv1.5 assembles into heterotetramers with Kv1.3 in macrophages and Kv1.2 in vascular smooth muscle, altering biophysical and pharmacological properties [PMID:11717161, PMID:17038323, PMID:18218624]. Loss-of-function KCNA5 mutations, including a dominant-negative truncation, cause atrial fibrillation through IKur loss and action potential prolongation [PMID:16772329, PMID:23264583], and Kv1.5 in vascular smooth muscle is required for H2O2-dependent coronary metabolic dilation [PMID:26224794].","teleology":[{"year":1993,"claim":"Establishing that Kv1.5 expression is transcriptionally regulated answered whether channel abundance is a dynamic, hormone-controlled variable rather than fixed.","evidence":"Nuclear run-on, mRNA stability, immunoblot and patch-clamp in dexamethasone-treated GH3 pituitary cells","pmids":["8352944"],"confidence":"Medium","gaps":["Mechanism in GH3 cells does not establish relevance to cardiac or vascular Kv1.5 regulation","Promoter elements mediating glucocorticoid induction not mapped"]},{"year":1995,"claim":"Defining the subcellular localization of Kv1.5 in human myocytes established where the channel operates within cardiac tissue.","evidence":"Immunofluorescence with two anti-channel antibodies and co-localization with connexin/N-cadherin in human atrial and ventricular myocytes","pmids":["7615797"],"confidence":"Medium","gaps":["Differential epitope accessibility between cardiac and vascular myocytes left unexplained","Single-lab antibody-based localization without genetic validation"]},{"year":1997,"claim":"Linking reduced Kv1.5 protein to reduced sustained K+ current in atrial fibrillation tissue established Kv1.5 as the molecular substrate of IKur and tied it to disease remodeling.","evidence":"Quantitative Western blot and perforated-patch recordings in human AF atrial appendages","pmids":["9168779"],"confidence":"Medium","gaps":["Correlation does not separate cause from consequence of AF remodeling","Mechanism of protein reduction not defined"]},{"year":1996,"claim":"Reconstituting Kvβ2.1/Kv1.5 and later Kvβ3.1/Kv1.5 co-assembly answered how auxiliary subunits tune Kv1.5 gating and inactivation.","evidence":"Cloning, immunopurification and patch-clamp of Kvβ2.1 (HEK293/L-cells) and Kvβ3.1 (CHO) co-expression","pmids":["8576199","9857044"],"confidence":"High","gaps":["Native stoichiometry of Kv1.5:Kvβ complexes in myocytes not determined","Structural basis of inactivation shift not resolved"]},{"year":1999,"claim":"Identifying PKA phosphorylation of Kvβ1.3 Ser24 and intracellular ion-coupled slow inactivation revealed how Kv1.5 inactivation is dynamically controlled by signaling and permeation.","evidence":"Charge-swap mutagenesis with PKA modulation in oocytes/HEK293, and ion-substitution patch-clamp with gating currents","pmids":["10318802","10050000"],"confidence":"High","gaps":["Whether these gating effects operate at physiological signaling levels in atrial myocytes not addressed","Slow inactivation mechanism shown to be non-classical but molecular pathway incomplete"]},{"year":2000,"claim":"Demonstrating Src-family kinase association and tyrosine phosphorylation of Kv1.5 established kinase control of channel activity beyond Kvβ-mediated effects.","evidence":"Co-IP, antisense, PP2, constitutively active Src and patch-clamp in astrocytes","pmids":["10884308"],"confidence":"Medium","gaps":["Direct phosphorylation site on Kv1.5 not mapped in this study","Relevance to cardiac Kv1.5 not tested"]},{"year":2001,"claim":"Identifying alpha-actinin-2 and SAP97 as anchoring partners answered how Kv1.5 is positioned and stabilized at the membrane.","evidence":"Yeast two-hybrid/in vitro binding mapping alpha-actinin-2 to Kv1.5 residues 73–148; co-IP, TDL motif mutagenesis and oocyte expression for SAP97","pmids":["11389904","11709425"],"confidence":"Medium","gaps":["Functional consequence of alpha-actinin-2 binding not quantified in 2001","SAP97 mechanism (PDZ-dependent vs indirect) not yet reconciled"]},{"year":2001,"claim":"Showing Kv1.2/Kv1.5 heterotetramers reproduce native vascular current established that Kv1.5 operates as a heteromeric channel in smooth muscle.","evidence":"Native vascular myocyte patch-clamp and tandem heterotetramer constructs in mammalian cells with pharmacology","pmids":["11717161"],"confidence":"Medium","gaps":["Native subunit stoichiometry inferred from tandem constructs","In vivo vascular role not yet established"]},{"year":2002,"claim":"Resolving PKA/cytoskeleton-dependent current maintenance, PKC/Kvβ1.2-dependent suppression, and external H+/Zn2+ pore inhibition mapped how Kv1.5 integrates kinase, cytoskeletal and extracellular regulatory inputs.","evidence":"PKA/phosphatase and alpha-actinin-2 antisense in oocytes; PMA/PKC inhibitor co-expression in HEK293; H463Q/R487V mutagenesis with gating currents","pmids":["11809852","12130714","12015417"],"confidence":"High","gaps":["Integration of these parallel pathways in native myocytes not addressed","Phosphatase identity in PKA maintenance not defined"]},{"year":2003,"claim":"Demonstrating SAP97 isoform-specific regulation and confirming Kv1.5 as the basis of canine atrial IKur clarified both anchoring control and the channel's identity as the IKur carrier.","evidence":"SAP97 isoform cloning, co-IP, imaging and patch-clamp; selective IKur blocker, RT-PCR, fractionation and AP recordings in canine atrial myocytes","pmids":["12970345","14500335"],"confidence":"High","gaps":["Whether SAP97 physically binds Kv1.5 remained contested (see 12860415)","Isoform balance in human disease not quantified"]},{"year":2003,"claim":"Reporting that SAP97 augments Kv1.5 current through an N-terminal, PDZ-independent and largely interaction-negative mechanism complicated the simple PDZ-anchoring model.","evidence":"N-/C-terminal deletion mutagenesis, yeast two-hybrid, co-IP and co-localization in HEK and myocytes, oocyte expression","pmids":["12860415"],"confidence":"Medium","gaps":["Physical interaction was largely undetectable, leaving the mechanism unresolved","Reconciliation with PDZ-dependent co-IP data not achieved"]},{"year":2005,"claim":"Identifying dynein/microtubule retrograde transport and proteasomal degradation answered how Kv1.5 surface levels are continuously opposed by removal and turnover pathways.","evidence":"p50/dynamitin, dynamin peptide, nocodazole, surface-accessibility and co-IP for dynein; pulse-chase with proteasome/lysosome inhibitors in COS and rat atrial cells","pmids":["16051887","16185660"],"confidence":"High","gaps":["E3 ligase mediating proteasomal targeting not identified in these studies","Coupling between retrograde transport and degradation not defined"]},{"year":2006,"claim":"Establishing Kv1.3/Kv1.5 heterotetramers in macrophages, 5-HT2A-driven internalization, and a dominant-negative AF truncation defined heteromeric assembly, receptor-triggered endocytosis, and the first disease mutation mechanism.","evidence":"FRET/co-IP heterotetramer assembly; 5-HT2A pharmacology and caveolar endocytosis in PASMC; E375X expression with dominant-negative testing, AP recordings and aminoglycoside rescue","pmids":["17038323","16527989","16772329"],"confidence":"High","gaps":["In vivo contribution of receptor-driven internalization to disease not established","Penetrance and frequency of E375X-type mutations not addressed by mechanism"]},{"year":2007,"claim":"Defining SUMOylation, S-acylation, Rab4/Rab11 recycling and cholesterol/caveolin-dependent trafficking built the core picture of how post-translational modification and endosomal sorting govern Kv1.5 surface density and gating.","evidence":"In vitro/in vivo SUMO assays with SENP2; hydroxylamine and cysteine mutagenesis for S-acylation; Rab4/Rab11 dominant-negative/constitutive mutants in HL-1; sucrose gradients and caveolin co-expression; methyl-β-cyclodextrin imaging in atrial myocytes","pmids":["17261810","17344312","17673464","18045854","17525113"],"confidence":"High","gaps":["Enzymes catalyzing Kv1.5 S-acylation not identified","How these modifications are coordinated in vivo not resolved","Caveolar dependence conflicts with negative caveolae findings (17054951)"]},{"year":2008,"claim":"Characterizing FHL1 and the NADPH-sensitive C-terminal Kvβ interface, plus SAP97 immobilization, Kv1.3 microdomain effects, and post-endocytic Rab sorting, expanded the C-terminal interactome and refined the trafficking map.","evidence":"GST pull-down/MS and co-IP for FHL1; C-terminal deletion and nucleotide-infusion patch-clamp for Kvβ; FRAP/imaging for SAP97 and Kv1.3 heterotetramers; Rab5/Rab4/Rab7 mutants in H9c2","pmids":["18281375","22426702","18245566","18218624","18755741"],"confidence":"High","gaps":["Structural model of the FHL1/Kv1.5 C-terminal complex not determined","Physiological metabolic conditions sensed by NADPH-dependent Kvβ regulation not defined"]},{"year":2009,"claim":"Localizing cholesterol-regulated trafficking to the Rab11 recycling endosome answered which endosomal pool cholesterol controls to set Kv1.5 surface levels.","evidence":"Patch-clamp, single-channel, FRAP, co-IP and Rab11/Rab4 dominant-negatives in adult rat atrial myocytes","pmids":["19706553"],"confidence":"High","gaps":["Molecular cholesterol sensor controlling exocytosis not identified","Link between membrane cholesterol and Rab11 machinery mechanistically unresolved"]},{"year":2012,"claim":"Identifying redox sulfenic acid modification of Cys581, AMPK/Nedd4-2 downregulation, and the PKC-dependent Kv1.5/Kvβ1.3/RACK1 channelosome connected oxidative and metabolic stress signaling to Kv1.5 trafficking and inactivation.","evidence":"DAz sulfenic acid probe and C581 mutagenesis with human AF tissue; AMPK mutant panel and Nedd4-2 co-expression in oocytes; co-IP/siRNA/inhibitor dissection of the PKC channelosome in HEK and rat tissue","pmids":["22843785","23221389","22547057"],"confidence":"High","gaps":["E3 ligase coupling redox modification to degradation not pinpointed","Whether AMPK acts through Nedd4-2 directly on Kv1.5 not proven"]},{"year":2015,"claim":"Genetic rescue showing vascular smooth muscle Kv1.5 is required for H2O2-dependent coronary metabolic dilation, plus urate/ROS/ERK upregulation and KCNA5 promoter methylation in cancer, broadened Kv1.5 function into vascular physiology and disease beyond the atrium.","evidence":"Kv1.5-null mice with smooth-muscle-specific rescue and in vivo/ex vivo vasoreactivity; URATv1/ROS/ERK pharmacology in HL-1; promoter methylation and decitabine in Ewing sarcoma","pmids":["26224794","26477273","26573141"],"confidence":"High","gaps":["Molecular link between H2O2 sensing and Kv1.5 activation in smooth muscle not defined","Role of KCNA5 silencing in tumor biology mechanistically thin"]},{"year":2012,"claim":"Cataloguing gain- and loss-of-function KCNA5 mutations in lone atrial fibrillation strengthened the causal genetic link and tied current changes to surface expression defects.","evidence":"KCNA5 sequencing, confocal surface-expression and patch-clamp of multiple mutants in transfected cells","pmids":["23264583"],"confidence":"Medium","gaps":["Trafficking defects of loss-of-function mutants not mechanistically dissected","In vivo arrhythmogenicity of individual variants not tested"]},{"year":null,"claim":"How the many parallel regulatory inputs — Kvβ subunits, kinase channelosomes, SUMO/S-acylation, redox modification, and Rab/cholesterol/dynein trafficking — are integrated to set Kv1.5 surface density and gating in a given cell type, and which E3 ligase couples modification to degradation, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model integrating modification, anchoring and trafficking inputs","Identity of the ubiquitin ligase targeting Kv1.5 not established","Molecular H2O2 sensor for vascular Kv1.5 activation unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[2,13,1,37]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,16,22,31,26]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[22,27,31]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[40,23]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[16,11]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2,13]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[16,22,27,31]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[21,23,40,33]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[19,36,2,33]}],"complexes":["Kv1.5/Kvβ channel complex","Kv1.5/Kv1.3 heterotetramer","Kv1.5/Kv1.2 heterotetramer","Kv1.5/Kvβ1.3/RACK1/PKC channelosome"],"partners":["KCNAB2","KCNAB3","KCNA3","KCNA2","DLG1","ACTN2","FHL1","RAB11A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P22460","full_name":"Potassium voltage-gated channel subfamily A member 5","aliases":["HPCN1","Voltage-gated potassium channel HK2","Voltage-gated potassium channel subunit Kv1.5"],"length_aa":613,"mass_kda":67.2,"function":"Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes. 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. Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel (PubMed:12130714). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation (PubMed:12130714). Homotetrameric channels display rapid activation and slow inactivation (PubMed:12130714, PubMed:8505626). Required for normal electrical conduction including formation of the infranodal ventricular conduction system and normal action potential configuration, as a result of its interaction with XIRP2 (By similarity). May play a role in regulating the secretion of insulin in normal pancreatic islets Exhibits a faster depolarization rate, reduced voltage-dependent recovery from inactivation and an excessive cumulative inactivation","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P22460/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KCNA5","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"IPO13","stoichiometry":0.2},{"gene":"POLR3E","stoichiometry":0.2},{"gene":"TMA16","stoichiometry":0.2},{"gene":"TOMM20A","stoichiometry":0.2},{"gene":"VDAC1","stoichiometry":0.2},{"gene":"VDAC3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KCNA5","total_profiled":1310},"omim":[{"mim_id":"621295","title":"CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY 1; CARASIL1","url":"https://www.omim.org/entry/621295"},{"mim_id":"612240","title":"ATRIAL FIBRILLATION, FAMILIAL, 7; ATFB7","url":"https://www.omim.org/entry/612240"},{"mim_id":"608583","title":"ATRIAL FIBRILLATION, FAMILIAL, 1; ATFB1","url":"https://www.omim.org/entry/608583"},{"mim_id":"604111","title":"POTASSIUM CHANNEL, VOLTAGE-GATED, SHAKER-RELATED SUBFAMILY, BETA MEMBER 3; KCNAB3","url":"https://www.omim.org/entry/604111"},{"mim_id":"601141","title":"POTASSIUM CHANNEL, VOLTAGE-GATED, SHAKER-RELATED SUBFAMILY, BETA MEMBER 1; KCNAB1","url":"https://www.omim.org/entry/601141"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":42.2},{"tissue":"choroid plexus","ntpm":57.3},{"tissue":"heart muscle","ntpm":36.5}],"url":"https://www.proteinatlas.org/search/KCNA5"},"hgnc":{"alias_symbol":["Kv1.5","HK2","HPCN1"],"prev_symbol":[]},"alphafold":{"accession":"P22460","domains":[{"cath_id":"3.30.710.10","chopping":"117-218","consensus_level":"high","plddt":94.487,"start":117,"end":218},{"cath_id":"1.20.120.350","chopping":"227-284_320-378_396-417","consensus_level":"medium","plddt":88.3729,"start":227,"end":417},{"cath_id":"1.10.287.70","chopping":"422-529","consensus_level":"high","plddt":94.607,"start":422,"end":529}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P22460","model_url":"https://alphafold.ebi.ac.uk/files/AF-P22460-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P22460-F1-predicted_aligned_error_v6.png","plddt_mean":71.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KCNA5","jax_strain_url":"https://www.jax.org/strain/search?query=KCNA5"},"sequence":{"accession":"P22460","fasta_url":"https://rest.uniprot.org/uniprotkb/P22460.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P22460/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P22460"}},"corpus_meta":[{"pmid":"2732228","id":"PMC_2732228","title":"Cytochrome P-450 hPCN3, a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver. cDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine.","date":"1989","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2732228","citation_count":507,"is_preprint":false},{"pmid":"9168779","id":"PMC_9168779","title":"Outward K+ current densities and Kv1.5 expression are reduced in chronic human atrial fibrillation.","date":"1997","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/9168779","citation_count":468,"is_preprint":false},{"pmid":"16772329","id":"PMC_16772329","title":"Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation.","date":"2006","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16772329","citation_count":381,"is_preprint":false},{"pmid":"18083891","id":"PMC_18083891","title":"Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1alpha-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer.","date":"2007","source":"American journal of physiology. 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Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/17040965","citation_count":29,"is_preprint":false},{"pmid":"26043299","id":"PMC_26043299","title":"PKC and AMPK regulation of Kv1.5 potassium channels.","date":"2015","source":"Channels (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/26043299","citation_count":28,"is_preprint":false},{"pmid":"15735608","id":"PMC_15735608","title":"Polymorphism screening in the cardiac K+ channel gene KCNA5.","date":"2005","source":"Clinical pharmacology and therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/15735608","citation_count":28,"is_preprint":false},{"pmid":"26569226","id":"PMC_26569226","title":"RETRACTED: Silencing of Kv1.5 Gene Inhibits Proliferation and Induces Apoptosis of Osteosarcoma Cells.","date":"2015","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26569226","citation_count":25,"is_preprint":false},{"pmid":"20858500","id":"PMC_20858500","title":"Celecoxib blocks cardiac Kv1.5, Kv4.3 and Kv7.1 (KCNQ1) channels: effects on cardiac action potentials.","date":"2010","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/20858500","citation_count":25,"is_preprint":false},{"pmid":"23185428","id":"PMC_23185428","title":"Involvement of Kv1.5 protein in oxidative vascular endothelial cell injury.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23185428","citation_count":24,"is_preprint":false},{"pmid":"24077947","id":"PMC_24077947","title":"Decreased Kv1.5 expression in intrauterine growth retardation rats with exaggerated pulmonary hypertension.","date":"2013","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/24077947","citation_count":24,"is_preprint":false},{"pmid":"28622331","id":"PMC_28622331","title":"In silico assessment of genetic variation in KCNA5 reveals multiple mechanisms of human atrial arrhythmogenesis.","date":"2017","source":"PLoS computational biology","url":"https://pubmed.ncbi.nlm.nih.gov/28622331","citation_count":23,"is_preprint":false},{"pmid":"22844358","id":"PMC_22844358","title":"Increased voltage-dependent K+ channel Kv1.3 and Kv1.5 expression correlates with leiomyosarcoma aggressiveness.","date":"2012","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/22844358","citation_count":23,"is_preprint":false},{"pmid":"22547057","id":"PMC_22547057","title":"Protein kinase C (PKC) activity regulates functional effects of Kvβ1.3 subunit on KV1.5 channels: identification of a cardiac Kv1.5 channelosome.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22547057","citation_count":23,"is_preprint":false},{"pmid":"26573141","id":"PMC_26573141","title":"Promoter Methylation Analysis Reveals That KCNA5 Ion Channel Silencing Supports Ewing Sarcoma Cell Proliferation.","date":"2015","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/26573141","citation_count":22,"is_preprint":false},{"pmid":"19519460","id":"PMC_19519460","title":"Kv1.5 blockers for the treatment of atrial fibrillation: approaches to optimization of potency and selectivity and translation to in vivo pharmacology.","date":"2009","source":"Current topics in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19519460","citation_count":22,"is_preprint":false},{"pmid":"18485768","id":"PMC_18485768","title":"Modeling the binding modes of Kv1.5 potassium channel and blockers.","date":"2008","source":"Journal of molecular graphics & modelling","url":"https://pubmed.ncbi.nlm.nih.gov/18485768","citation_count":22,"is_preprint":false},{"pmid":"11997261","id":"PMC_11997261","title":"Direct inhibition of the cloned Kv1.5 channel by AG-1478, a tyrosine kinase inhibitor.","date":"2002","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/11997261","citation_count":22,"is_preprint":false},{"pmid":"17266934","id":"PMC_17266934","title":"Mutations in the Kv1.5 channel gene KCNA5 in cardiac arrest patients.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17266934","citation_count":21,"is_preprint":false},{"pmid":"18984061","id":"PMC_18984061","title":"Hypoxia suppresses KV1.5 channel expression through endogenous 15-HETE in rat pulmonary artery.","date":"2008","source":"Prostaglandins & other lipid mediators","url":"https://pubmed.ncbi.nlm.nih.gov/18984061","citation_count":21,"is_preprint":false},{"pmid":"28011270","id":"PMC_28011270","title":"H2S inhibits angiotensin II-induced atrial Kv1.5 upregulation by attenuating Nox4-mediated ROS generation during atrial fibrillation.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28011270","citation_count":21,"is_preprint":false},{"pmid":"30218748","id":"PMC_30218748","title":"5-HTT, BMPR2, EDN1, ENG, KCNA5 gene polymorphisms and susceptibility to pulmonary arterial hypertension: A meta-analysis.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/30218748","citation_count":20,"is_preprint":false},{"pmid":"18281375","id":"PMC_18281375","title":"Four and a half LIM protein 1: a partner for KCNA5 in human atrium.","date":"2008","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/18281375","citation_count":20,"is_preprint":false},{"pmid":"24632326","id":"PMC_24632326","title":"Pharmacology of voltage-gated potassium channel Kv1.5--impact on cardiac excitability.","date":"2014","source":"Current opinion in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24632326","citation_count":20,"is_preprint":false},{"pmid":"35521179","id":"PMC_35521179","title":"Chemical and biological study of aplysiatoxin derivatives showing inhibition of potassium channel Kv1.5.","date":"2019","source":"RSC advances","url":"https://pubmed.ncbi.nlm.nih.gov/35521179","citation_count":20,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56528,"output_tokens":11581,"usd":0.17165,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":22354,"output_tokens":6919,"usd":0.142373,"stage2_stop_reason":"end_turn"},"total_usd":0.314023,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Kv1.5 protein localizes to intercalated disk regions in human atrial and ventricular myocytes, as determined by co-localization with connexin and N-cadherin antibodies; NH2-terminal antibodies additionally stained vascular smooth muscle, suggesting differential epitope accessibility between cardiac and vascular myocytes.\",\n      \"method\": \"Immunofluorescence with two distinct anti-channel antibodies, co-localization with connexin and N-cadherin markers\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment in human cardiac tissue with two antibodies and co-localization controls, single lab\",\n      \"pmids\": [\"7615797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The Kvβ2.1 subunit co-assembles with hKv1.5 alpha subunit, shifting the midpoints for activation (~14 mV negative) and inactivation (~12 mV negative) and increasing the extent of slow inactivation, thereby altering Kv1.5 gating kinetics.\",\n      \"method\": \"Molecular cloning, immunopurification, Western blot, whole-cell patch-clamp in HEK293 and L-cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in multiple cell lines, molecular cloning, and functional electrophysiology with multiple orthogonal methods in one study\",\n      \"pmids\": [\"8576199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Kv1.5 protein expression is reduced by >50% in both left and right atrial appendages of patients with chronic atrial fibrillation, in parallel with a reduction in sustained (IKsus/IKur) outward K+ current density, consistent with Kv1.5 underlying IKur.\",\n      \"method\": \"Quantitative Western blot, nystatin-perforated patch-clamp recordings of atrial myocytes\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (Western blot + patch-clamp) in human tissue, single lab\",\n      \"pmids\": [\"9168779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Co-expression of human Kvβ3.1 with Kv1.5 in Chinese hamster ovary cells produces a novel fast-inactivating (A-type) outward current, demonstrating that Kvβ3.1 confers rapid inactivation on Kv1.5.\",\n      \"method\": \"Heterologous co-expression in CHO cells, whole-cell patch-clamp\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution with electrophysiology, single lab\",\n      \"pmids\": [\"9857044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PKA phosphorylation of serine-24 on the Kvβ1.3 NH2-terminus reduces Kvβ1.3-induced fast inactivation of Kv1.5; substitution of serine-24 with a negatively charged residue mimics phosphorylation (reduces inactivation) while a positively charged residue enhances inactivation.\",\n      \"method\": \"Site-directed mutagenesis of Kvβ1.3 serine-24, patch-clamp in Xenopus oocytes and HEK293 cells, PKA activation/inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis with charge-swap validation, two heterologous expression systems, multiple orthogonal experiments in one study\",\n      \"pmids\": [\"10318802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Slow inactivation of hKv1.5 is regulated by intracellular ion occupancy: intracellular K+ (or Cs+) concentration modulates inactivation with low affinity (Kd ~34–43 mM), and this is more potent than extracellular ion effects; the inactivation mechanism is not classical C-type but is closely coupled to ion permeation through the pore.\",\n      \"method\": \"Whole-cell patch-clamp with varied intra- and extracellular cation concentrations, including symmetric reduction experiments and gating current analysis\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biophysical assay with multiple ion conditions, single lab\",\n      \"pmids\": [\"10050000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Kv1.5 is associated with Src family protein tyrosine kinases in astrocytes (demonstrated by co-immunoprecipitation); Src-mediated tyrosine phosphorylation of Kv1.5 is required for full channel activity and astrocyte proliferation, and this phosphorylation is downregulated during differentiation.\",\n      \"method\": \"Co-immunoprecipitation, antisense oligodeoxynucleotides, Src-specific inhibitor PP2, constitutively active Src transfection, whole-cell patch-clamp\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional electrophysiology and genetic manipulation, single lab\",\n      \"pmids\": [\"10884308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Alpha-actinin-2 binds to a discrete region (amino acids 73–148) of the Kv1.5 N-terminus via its internal spectrin repeats, as demonstrated by yeast two-hybrid and in vitro binding assays; this interaction does not occur with Kv1.1, Kv1.2, or Kv1.3 N-termini.\",\n      \"method\": \"Yeast two-hybrid analysis, in vitro binding assays, deletion analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal binding methods with domain deletion mapping, single lab\",\n      \"pmids\": [\"11389904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SAP97 co-localizes and co-immunoprecipitates with Kv1.5 in cardiac myocytes at intercalated disks and lateral membranes; the C-terminal PDZ-binding motif (TDL) of Kv1.5 is required for this interaction, and SAP97 co-expression augments Kv1.5 currents in Xenopus oocytes.\",\n      \"method\": \"Co-immunoprecipitation, immunocytochemistry, site-directed mutagenesis (TDL→AAA), functional expression in Xenopus oocytes\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and mutagenesis in multiple systems, single lab\",\n      \"pmids\": [\"11709425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Heteromultimeric Kv1.2/Kv1.5 channels underlie the 4-AP-sensitive delayed rectifier K+ current in rabbit portal vein vascular myocytes; tandem-coupled [Kv1.5/Kv1.2]2 heterotetramers reproduced the characteristic voltage-dependent shift in activation seen in native channels but absent in Kv1.5 homotetramers.\",\n      \"method\": \"Patch-clamp of native vascular myocytes, heterologous expression of homo- and heterotetramers (including tandem constructs) in mammalian cells, pharmacological characterization\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tandem construct and functional pharmacology, single lab\",\n      \"pmids\": [\"11717161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"External H+ and Zn2+ inhibit hKv1.5 by stabilizing an inactivated state; this inhibition requires histidine H463 (in the channel turret) and R487 (near the outer pore mouth), and is relieved by extracellular K+ through a non-competitive mechanism.\",\n      \"method\": \"Site-directed mutagenesis (H463Q, R487V), whole-cell patch-clamp, gating current analysis in non-conducting mutant hKv1.5 W472F, varied extracellular [K+]\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of multiple residues combined with gating current analysis and ionic substitution in a single rigorous study\",\n      \"pmids\": [\"12015417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PKA activity is required to maintain Kv1.5 current levels; inhibition of PKA reduces Kv1.5 currents by revealing endogenous phosphatase activity, and this regulation requires an intact actin cytoskeleton and alpha-actinin-2 (antisense knockdown of alpha-actinin-2 abolishes the effect).\",\n      \"method\": \"Xenopus oocyte expression, PKA activators/inhibitors, cytochalasin (actin disruption), phalloidin, antisense oligonucleotides against alpha-actinin-2, alkaline phosphatase injection, orthovanadate\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological interventions and antisense KD in single lab\",\n      \"pmids\": [\"11809852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PKC activation (via PMA) markedly reduces Kv1.5 current only when Kv1.5 is co-expressed with Kvβ1.2 (but not Kvβ1.3); all three proteins (Kv1.5, Kvβ1.2, Kvβ1.3) are substrates for PKC phosphorylation, and Kv1.5 assembles in vivo with both beta subunits.\",\n      \"method\": \"Co-expression in HEK293 cells, whole-cell patch-clamp, phorbol ester activation, PKC inhibitors, in vivo assembly demonstrated\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology with pharmacological controls and subunit co-assembly evidence, single lab\",\n      \"pmids\": [\"12130714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Kv1.5 is the molecular basis of IKur in canine atrial myocytes; a Kv1.5-selective compound (not affecting Kv3.1, hERG, or sodium channels) fully suppressed IKur tail currents and prolonged atrial action potentials, while Kv3.1 protein was undetectable in atrial membrane fractions.\",\n      \"method\": \"RT-PCR, Western blot of cytosolic and membrane fractions, confocal immunostaining, voltage-clamp, action potential recordings in isolated canine atrial myocytes\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (molecular + functional + pharmacological) replicated across modalities in one study\",\n      \"pmids\": [\"14500335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Different SAP97 isoforms differentially regulate Kv1.5: the cardiac isoform lacking I1A insert increases Kv1.5 current (215%) and promotes surface membrane clustering, while the isoform containing I1A abolishes this effect; both isoforms co-immunoprecipitate with Kv1.5.\",\n      \"method\": \"RT-PCR isoform cloning, co-immunoprecipitation, confocal imaging of GFP-tagged channels, patch-clamp in CHO cells, W623F SH3-domain mutation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, mutagenesis, imaging, and functional electrophysiology, single lab\",\n      \"pmids\": [\"12970345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SAP97 increases hKv1.5 current through an indirect mechanism dependent on the Kv1.5 N-terminus (not the C-terminal PDZ-binding motif); no physical interaction between SAP97 and Kv1.5 could be detected by co-IP, co-localization, or yeast two-hybrid in most experiments.\",\n      \"method\": \"Deletion mutagenesis of Kv1.5 N- and C-termini, yeast two-hybrid, co-IP from HEK cells and rat ventricular myocytes, co-localization in cardiac myocytes, Xenopus oocyte functional expression\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus multiple interaction assays, single lab; notably, physical interaction was largely negative\",\n      \"pmids\": [\"12860415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Kv1.5 surface expression is regulated by retrograde trafficking via the dynein motor complex: disruption of dynein-dynactin (by p50/dynamitin overexpression), inhibition of endocytosis (dynamin inhibitory peptide), or microtubule depolymerization (nocodazole) all increase Kv1.5 current density and redistribute channels to the plasma membrane; Kv1.5 co-immunoprecipitates with the dynein motor complex in an interaction requiring the N-terminal SH3-binding domain.\",\n      \"method\": \"Overexpression of p50/dynamitin, dynamin inhibitory peptide, nocodazole, Proteinase K surface accessibility assay, co-immunoprecipitation, confocal imaging in HEK cells and rat atrial myocytes, patch-clamp\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional and biochemical methods in two cell systems, with domain-mapping of the interaction\",\n      \"pmids\": [\"16051887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Kv1.5 is internalized upon activation of 5-HT2A receptors by serotonin via a pathway involving phospholipase C, protein kinase C, tyrosine kinases, and caveolae-mediated endocytosis; 5-HT2A receptors and caveolin-1 co-immunoprecipitate with Kv1.5 channels in pulmonary artery homogenates.\",\n      \"method\": \"Co-immunoprecipitation, pharmacological inhibitors (ketanserin, U73122, Gö6976, genistein, tyrphostin 23, beta-cyclodextrin, concanavalin A), patch-clamp, confocal imaging of channel internalization in rat PASMC and Ltk- cells stably expressing hKv1.5\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus pharmacological dissection and functional electrophysiology, single lab\",\n      \"pmids\": [\"16527989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Kv1.5 and Kv1.3 form functional heterotetramers in macrophages; co-expression of Kv1.5 positively shifts K+ current half-activation voltage, both subunits co-immunoprecipitate and co-localize at the membrane, and FRET studies confirm heterotetrameric assembly; TNF-α activation increases Kv1.3 without changing Kv1.5, altering the pharmacological profile.\",\n      \"method\": \"Co-immunoprecipitation, co-localization by microscopy, FRET, Xenopus oocyte co-expression with varied subunit ratios, HEK293 co-expression, electrophysiology, pharmacology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — FRET plus co-IP plus functional reconstitution in multiple systems, multiple orthogonal methods\",\n      \"pmids\": [\"17038323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A nonsense mutation (E375X) in KCNA5 truncates Kv1.5 at the S4-S6 voltage sensor, pore, and C-terminus; heterologously expressed E375X fails to generate IKur and exerts a dominant-negative effect on wild-type current, leading to action potential prolongation and early afterdepolarizations in human atrial myocytes. Aminoglycoside-induced translational read-through of the premature stop codon rescues channel function.\",\n      \"method\": \"Genomic DNA scanning, heterologous expression, whole-cell patch-clamp, action potential recordings in human atrial myocytes, murine in vivo model, aminoglycoside read-through rescue\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutation characterization with functional reconstitution, dominant-negative assessment, native cell AP recordings, and pharmacological rescue in one study\",\n      \"pmids\": [\"16772329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"AVE0118 blocks Kv1.5 by binding to the inner cavity of the channel pore; alanine-scanning mutagenesis identified Thr479, Thr480, Val505, Ile508, Val512, and Val516 (facing the central cavity) and Ile502 and Leu510 (facing away from cavity) as key binding residues; block is open-state preferring and slows current deactivation ('foot-in-the-door' mechanism).\",\n      \"method\": \"Alanine-scanning mutagenesis of the pore domain, two-microelectrode voltage-clamp in Xenopus oocytes, homology model docking\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic alanine-scanning mutagenesis combined with functional electrophysiology and structural docking in a single study\",\n      \"pmids\": [\"16835355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Kv1.5 is post-translationally modified by SUMO-1, -2, and -3 at two membrane-proximal cytoplasmic SUMO consensus sites; Kv1.5 interacts specifically with the SUMO-conjugating enzyme Ubc9 and serves as a substrate in a minimal in vitro reconstituted SUMOylation reaction; disruption of SUMOylation sites or expression of SUMO protease SENP2 causes a ~15 mV hyperpolarizing shift in the voltage dependence of steady-state inactivation.\",\n      \"method\": \"In vitro reconstituted SUMOylation assay, in vivo SUMOylation with SUMO-specific protease deconjugation (SENP2, Ulp1), mutagenesis of SUMO target motifs, whole-cell patch-clamp\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution plus mutagenesis plus functional electrophysiology, multiple orthogonal methods in one study\",\n      \"pmids\": [\"17261810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Rab4- and Rab11-dependent endosomal recycling pathways regulate steady-state Kv1.5 surface levels in atrial myocytes: Kv1.5 internalizes to EEA1-positive early endosomes and recycles back to the plasma membrane; dominant-negative Rab4S22N and Rab11S25N decrease surface Kv1.5 levels while GTPase-deficient Rab4Q67L and Rab11Q70L increase them; Rab11 co-immunoprecipitates with Kv1.5.\",\n      \"method\": \"Kinetic internalization assays, co-localization with endosomal markers, co-immunoprecipitation, dominant-negative and constitutively active Rab GTPase mutants, live-cell surface labeling, electrophysiology in HL-1 mouse atrial myocytes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple Rab mutants with reciprocal functional effects, co-IP, and kinetic studies in atrial myocytes\",\n      \"pmids\": [\"17673464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"S-acylation (palmitoylation) of Kv1.5 on COOH-terminal cysteines via hydroxylamine-sensitive thioester bonds is required for normal surface expression; pharmacological inhibition of S-acylation decreases surface Kv1.5 and targets it for proteasomal degradation; S-acylation occurs in the biosynthetic pathway of nascent channel protein.\",\n      \"method\": \"Hydroxylamine treatment, inhibitors of S-acylation, proteasome inhibitors, COOH-terminal cysteine mutation, confocal microscopy, Western blot in transfected fibroblasts\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical demonstration of thioester bond, mutagenesis of cysteines, and functional consequence in single lab\",\n      \"pmids\": [\"17344312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Caveolin is required for trafficking of Kv1.5 to cholesterol-rich lipid raft microdomains; in cells lacking endogenous caveolin, Kv1.5 association with low-density detergent-resistant membranes requires exogenous caveolin co-expression; caveolin-trafficking mutants sequester Kv1.5 in intracellular compartments, reducing surface channel expression; caveolin co-expression induces depolarizing shifts in Kv1.5 activation and inactivation analogous to elevated cholesterol effects.\",\n      \"method\": \"Sucrose gradient fractionation, co-expression with caveolin and caveolin trafficking mutants, whole-cell patch-clamp, confocal microscopy\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical and functional approaches, single lab\",\n      \"pmids\": [\"18045854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Membrane cholesterol depletion (via methyl-β-cyclodextrin) causes redistribution of Kv1.5 subunits from cholesterol-enriched microdomains into larger clusters throughout the plasma membrane, increasing IKur current; Kv1.5 subunits are concentrated in cholesterol-rich microdomains distinct from caveolae in rat atrial cardiomyocytes.\",\n      \"method\": \"Methyl-β-cyclodextrin treatment, GFP-tagged Kv1.5 imaging in live neonatal cardiomyocytes, sucrose gradient fractionation, patch-clamp in rat atrial myocytes, cholesterol loading with LDL\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging with functional electrophysiology, single lab\",\n      \"pmids\": [\"17525113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SAP97 retains and immobilizes Kv1.5 subunits in the plasma membrane of cardiac myocytes, increasing IKur current density and reducing channel mobility (FRAP); SAP97 overexpression clusters endogenous Kv1.5 at myocyte-myocyte contacts.\",\n      \"method\": \"Adenovirus-mediated SAP97 overexpression in rat neonatal cardiomyocytes and CHO cells, FRAP, immunocytochemistry, whole-cell patch-clamp, cell-attached patch recordings\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP plus functional electrophysiology plus imaging, single lab\",\n      \"pmids\": [\"18245566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"After internalization, Kv1.5 rapidly associates with Rab5- and Rab4-positive early endosomes (fast recycling pathway), and a fraction is targeted to Rab7-positive late endosomes for degradation; Rab5DN increases Kv1.5 current ~2-fold, Rab4DN similarly increases currents, Rab7 overexpression decreases currents in H9c2 myoblasts; Rab11-positive perinuclear recycling is slow and only evident after 24 h.\",\n      \"method\": \"Dominant-negative and constitutively active Rab GTPase mutants, post-internalization trafficking assays, co-localization with endosomal markers, whole-cell patch-clamp in H9c2 myoblasts and HEK293 cells\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple Rab mutants with reciprocal effects, co-localization studies, single lab\",\n      \"pmids\": [\"18755741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The C-terminal domain of Kv1.5 (specifically Arg543-Val583) interacts with Kvβ subunits in a pyridine-nucleotide-dependent manner: NADPH accelerates Kvβ3-induced inactivation while NADP+ reverses it; deletion of the C-terminus abolishes nucleotide-sensitive Kvβ regulation; a GST-C-terminal fusion protein binds Kvβ2:NADPH with higher affinity than Kvβ2:NADP+.\",\n      \"method\": \"C-terminal deletion mutagenesis, GST pull-down with brain lysates, patch-clamp with intrapipette nucleotide infusion, co-expression in COS-7 cells\",\n      \"journal\": \"Pflugers Archiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — GST pull-down plus mutagenesis plus functional electrophysiology, single lab\",\n      \"pmids\": [\"22426702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Four-and-a-half LIM protein 1 (FHL1) physically interacts with the Kv1.5/KCNA5 C-terminal domain in human atrium; co-expression of FHL1 markedly increases Kv1.5 current density and shifts activation to more positive potentials, and increases the extent and rate of slow inactivation.\",\n      \"method\": \"GST-KCNA5 C-terminal pull-down with mass spectrometry, co-immunoprecipitation from human atrium and CHO cells, confocal microscopy, patch-clamp in CHO cells\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — GST pull-down with MS identification, co-IP in native tissue, and functional reconstitution, multiple orthogonal methods\",\n      \"pmids\": [\"18281375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Kv1.3 association modifies Kv1.5 trafficking: Kv1.3/Kv1.5 heterotetramers (confirmed by FRET) target to distinct surface microdomains with higher lateral mobility than Kv1.3 homotetramers; immunoprecipitation shows heteromeric channels associate with caveolar raft domains differently from Kv1.3 homomers; FRAP reveals higher mobility for hybrid channels.\",\n      \"method\": \"FRET, FRAP, co-immunoprecipitation, cholesterol depletion, caveolae co-localization, pharmacology in HEK cells and LPS-activated macrophages\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET and FRAP plus co-IP, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"18218624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cholesterol regulates Kv1.5 surface expression by modulating trafficking through the Rab11-associated recycling endosome: cholesterol depletion promotes exocytosis of Kv1.5 from a Rab11-positive intracellular pool; dominant-negative Rab11 (but not Rab4) prevents the cholesterol depletion-induced increase in IKur; Rab11 co-immunoprecipitates with hKv1.5-EGFP.\",\n      \"method\": \"Whole-cell patch-clamp, single-channel recordings, FRAP, 3D microscopy, co-immunoprecipitation, dominant-negative Rab11 and Rab4 mutants, NEM and GTP-γ-S inhibitors in rat adult atrial myocytes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, dominant negatives, single-channel, FRAP) in native atrial myocytes\",\n      \"pmids\": [\"19706553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A novel 33-bp coding region deletion in the Kv1.5 N-terminus (removing 11 amino acids including an SH3-domain binding site for Src-family tyrosine kinases) causes ~60% reduction in IKur and a dominant-negative effect; pretreatment with Src inhibitor PP2 prevents v-Src from suppressing wild-type current, whereas the mutant channel is unresponsive to v-Src, implicating tyrosine kinase signaling through the N-terminal SH3-binding domain in Kv1.5 regulation.\",\n      \"method\": \"Site-directed mutagenesis, transfection in cells, whole-cell patch-clamp, Src inhibitor PP2, v-Src kinase treatment\",\n      \"journal\": \"Heart rhythm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional electrophysiology with pharmacological Src inhibition and mutant characterization, single lab\",\n      \"pmids\": [\"20638934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Oxidative stress leads to sulfenic acid modification of Kv1.5 on a single C-terminal cysteine (C581); this modification is necessary and sufficient to reduce channel surface expression, promote internalization, and block recycling; under prolonged oxidative stress, sulfenic acid modification triggers channel degradation. Sulfenic acid-modified proteins including Kv1.5 are elevated in human atrial fibrillation.\",\n      \"method\": \"Sulfenic acid-specific probe (DAz) labeling with Western blot, site-directed mutagenesis of C581, live-cell immunofluorescence, whole-cell voltage-clamp, Western blot in human AF tissue\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — chemical probe labeling, cysteine mutagenesis, and functional trafficking assays with human disease tissue validation\",\n      \"pmids\": [\"22843785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"AMPK activation (wild-type and constitutively active γR70Q, but not inactive αK45R mutant) significantly reduces Kv1.5-mediated K+ currents and decreases Kv1.5 protein abundance in the cell membrane; Nedd4-2 co-expression similarly downregulates Kv1.5 currents, suggesting AMPK acts in part via Nedd4-2.\",\n      \"method\": \"Xenopus oocyte injection with Kv1.5 ± AMPK constructs, two-electrode voltage-clamp, chemiluminescence and confocal microscopy for membrane protein abundance\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional electrophysiology with AMPK mutant panel and Nedd4-2 co-expression, single lab\",\n      \"pmids\": [\"23221389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PKC activity is required for Kvβ1.3-induced fast inactivation of Kv1.5; PKC inhibition (calphostin C or siRNA knockdown of all PKC isoforms) abolishes fast inactivation without dissociating Kv1.5 from Kvβ1.3 (co-IP and co-localization preserved); a Kv1.5 channelosome comprising Kv1.5, Kvβ1.3, RACK1, PKCβI, PKCβII, and PKCθ was identified by co-immunoprecipitation in HEK293 cells and rat ventricular tissue.\",\n      \"method\": \"Co-immunoprecipitation, immunocytochemistry, siRNA knockdown of PKC isoforms, calphostin C inhibition, whole-cell patch-clamp, rat ventricular and atrial tissue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP in native tissue, siRNA knockdown, pharmacological inhibition, and electrophysiology, multiple orthogonal methods\",\n      \"pmids\": [\"22547057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Novel gain-of-function (E48G, A305T, D322H) and loss-of-function (Y155C, D469E, P488S) mutations in KCNA5 were identified in patients with early-onset lone atrial fibrillation; loss-of-function mutants showed decreased surface expression by confocal microscopy, while gain-of-function mutants showed preserved surface expression with increased IKur.\",\n      \"method\": \"Sequencing of KCNA5, confocal microscopy for surface expression, whole-cell patch-clamp in transfected cells\",\n      \"journal\": \"European heart journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional characterization of multiple mutations with imaging and electrophysiology, single lab\",\n      \"pmids\": [\"23264583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Kv1.5 channels in vascular smooth muscle are required for coronary metabolic dilation: Kv1.5-null mice show impaired myocardial blood flow and tissue oxygen tension during cardiac stress despite elevated cardiac work; smooth muscle-specific re-expression of Kv1.5 in the null background rescues metabolic dilation; isolated arteries from Kv1.5-null mice show impaired relaxation to H2O2 but normal responses to adenosine and acetylcholine.\",\n      \"method\": \"Kv1.5 knockout mice, inducible smooth muscle-specific Kv1.5 rescue transgene, in vivo hemodynamic and blood flow measurements (micromanometer catheters), myocardial tissue oxygen tension, isolated artery vasoreactivity studies\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with rescue by smooth muscle-specific re-expression, in vivo and ex vivo functional measurements\",\n      \"pmids\": [\"26224794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Urate taken up intracellularly via URATv1 increases Kv1.5 protein expression and IKur in HL-1 atrial myocytes through NADPH oxidase-derived reactive oxygen species and ERK phosphorylation; the ERK inhibitor PD98059 and antioxidants (NAC, apocynin) abolish the urate-induced increase in Kv1.5.\",\n      \"method\": \"URATv1 inhibitor (benzbromarone), ABCG2 inhibitor (KO143), N-acetylcysteine, apocynin, ERK inhibitor PD98059, ROS flow cytometry, RT-PCR, immunoblot, patch-clamp in HL-1 cells\",\n      \"journal\": \"Circulation journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with multiple inhibitors and functional electrophysiology, single lab\",\n      \"pmids\": [\"26477273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DNA methylation of the KCNA5 promoter epigenetically silences Kv1.5 channel expression in Ewing sarcoma cells; treatment with the DNA methylation inhibitor decitabine restores Kv1.5 expression and inhibits Ewing sarcoma cell proliferation.\",\n      \"method\": \"Promoter methylation analysis, decitabine treatment, Kv1.5 expression assays, cell proliferation assays\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — methylation-restoration with functional proliferation readout, single lab\",\n      \"pmids\": [\"26573141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Kv1.5 is degraded by the proteasome: proteasome inhibitors (MG132, ALLN, lactacystine) prolong Kv1.5 half-life (~6.7 h), increase ubiquitinated Kv1.5 levels, and increase IKur by stabilizing channel protein in the ER/Golgi; lysosomal inhibition has no effect; this degradation pathway was also demonstrated in endogenous Kv1.5 in rat atrial cells.\",\n      \"method\": \"Pulse-chase analysis, proteasome and lysosomal inhibitors, immunofluorescence, patch-clamp, brefeldin A and colchicine treatment in COS cells and rat atrial cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulse-chase plus pharmacological inhibitors plus functional electrophysiology in two cell systems, single lab\",\n      \"pmids\": [\"16185660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Kv1.5 does not localize to caveolae in rat and canine cardiac myocytes: co-immunoprecipitation of Kv1.5 with caveolin-3 was not detected (though caveolin-3/eNOS and caveolin-3/β-dystroglycan interactions were), and wide-field/deconvolution microscopy showed <12% co-localization of Kv1.5 with caveolin-3 in atrial myocytes; in HEK293 cells Kv1.5 does not partition into low-buoyancy raft fractions.\",\n      \"method\": \"Co-immunoprecipitation, wide-field microscopy with deconvolution, immunoelectron microscopy, sucrose gradient fractionation in rat and canine cardiac tissue and HEK293 cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple negative co-localization/co-IP methods with positive controls, single lab; notable negative finding for caveolae association\",\n      \"pmids\": [\"17054951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Dexamethasone (glucocorticoid) rapidly induces Kv1.5 gene transcription in GH3 pituitary cells, increasing Kv1.5 mRNA and ~3-fold increasing Kv1.5 protein (76 kDa, t1/2 ~4 hr) within 12 h, which is associated with increased noninactivating voltage-gated K+ current; Kv1.5 mRNA turnover (t1/2 ~0.5 hr) is not affected.\",\n      \"method\": \"Nuclear run-on transcription assay, mRNA stability assay, immunoblot, whole-cell patch-clamp in GH3 cells\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcription run-on plus protein quantification plus functional electrophysiology, single lab\",\n      \"pmids\": [\"8352944\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Kv1.5 (KCNA5) is a voltage-gated K+ channel alpha-subunit that underlies the ultrarapid delayed rectifier current IKur in human atrial myocytes and regulates membrane potential in vascular smooth muscle; its function and surface expression are governed by a multi-layered regulatory network including: co-assembly with Kvβ subunits (Kvβ1.2, Kvβ1.3, Kvβ2.1, Kvβ3.1) that modulate inactivation kinetics; phosphorylation by PKA (via Kvβ1.3 Ser24), PKC (requiring Kvβ1.2 co-expression), and Src-family tyrosine kinases (via N-terminal SH3-binding domain); post-translational modifications by SUMOylation (shifting inactivation voltage dependence) and S-acylation (required for biosynthetic trafficking); redox-sensitive sulfenic acid modification of C-terminal C581 (triggering internalization and degradation under oxidative stress); and dynamic trafficking through Rab5/Rab4-mediated endocytosis, Rab4/Rab11-dependent recycling, and dynein-dependent retrograde transport along microtubules, with cholesterol-dependent recruitment from Rab11-positive recycling endosomes; anchoring proteins including SAP97 (via indirect N-terminal mechanism), FHL1 (C-terminal interaction increasing current and altering gating), and alpha-actinin-2 (N-terminal interaction) regulate surface expression and localization; Kv1.5 forms heterotetramers with Kv1.3 in macrophages and Kv1.2 in vascular smooth muscle, altering biophysical and pharmacological properties; loss-of-function mutations cause atrial fibrillation through action potential prolongation, while the channel is also essential for H2O2-sensitive coronary metabolic dilation in vascular smooth muscle.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KCNA5 encodes Kv1.5, a voltage-gated K+ channel alpha-subunit that underlies the ultrarapid delayed rectifier current IKur in atrial myocytes and controls membrane potential in vascular smooth muscle [#2, #13, #37]. In the heart it localizes to intercalated disk regions and lateral membranes [#0, #8], where it forms the molecular basis of atrial IKur and shapes the atrial action potential [#13]. Channel gating and inactivation are extensively tuned by co-assembled Kvβ subunits — Kvβ2.1 shifts activation and inactivation voltage dependence and enhances slow inactivation [#1], Kvβ3.1 confers fast A-type inactivation [#3], and Kvβ regulation is read out through the channel C-terminus in a pyridine-nucleotide (NADPH/NADP+)-dependent manner [#28]. This Kvβ-conferred inactivation is itself a signaling node: PKA phosphorylation of Kvβ1.3 Ser24 reduces fast inactivation [#4], while PKC activity is required for Kvβ1.3-induced fast inactivation within a defined Kv1.5/Kvβ1.3/RACK1/PKC channelosome [#12, #35]. Surface density is set by a multilayered trafficking and modification network: S-acylation of C-terminal cysteines is needed for biosynthetic delivery [#23], SUMOylation at membrane-proximal sites shifts inactivation voltage dependence [#21], and the channel is internalized through Rab5/Rab4 early endosomes and recycled via Rab4/Rab11 pathways, with dynein-dependent retrograde transport along microtubules and cholesterol-sensitive recruitment from Rab11-positive recycling endosomes opposing surface expression [#16, #22, #27, #31]. Oxidative stress drives sulfenic acid modification of C-terminal Cys581, which promotes internalization, blocks recycling, and targets the channel for degradation, a modification elevated in human atrial fibrillation [#33]. Anchoring partners FHL1 (C-terminal) and alpha-actinin-2 (N-terminal) increase current and modulate gating and localization [#7, #29], and SAP97 increases IKur and clusters/immobilizes channels at cell-cell contacts [#8, #14, #26]. Kv1.5 assembles into heterotetramers with Kv1.3 in macrophages and Kv1.2 in vascular smooth muscle, altering biophysical and pharmacological properties [#9, #18, #30]. Loss-of-function KCNA5 mutations, including a dominant-negative truncation, cause atrial fibrillation through IKur loss and action potential prolongation [#19, #36], and Kv1.5 in vascular smooth muscle is required for H2O2-dependent coronary metabolic dilation [#37].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing that Kv1.5 expression is transcriptionally regulated answered whether channel abundance is a dynamic, hormone-controlled variable rather than fixed.\",\n      \"evidence\": \"Nuclear run-on, mRNA stability, immunoblot and patch-clamp in dexamethasone-treated GH3 pituitary cells\",\n      \"pmids\": [\"8352944\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism in GH3 cells does not establish relevance to cardiac or vascular Kv1.5 regulation\", \"Promoter elements mediating glucocorticoid induction not mapped\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Defining the subcellular localization of Kv1.5 in human myocytes established where the channel operates within cardiac tissue.\",\n      \"evidence\": \"Immunofluorescence with two anti-channel antibodies and co-localization with connexin/N-cadherin in human atrial and ventricular myocytes\",\n      \"pmids\": [\"7615797\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Differential epitope accessibility between cardiac and vascular myocytes left unexplained\", \"Single-lab antibody-based localization without genetic validation\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Linking reduced Kv1.5 protein to reduced sustained K+ current in atrial fibrillation tissue established Kv1.5 as the molecular substrate of IKur and tied it to disease remodeling.\",\n      \"evidence\": \"Quantitative Western blot and perforated-patch recordings in human AF atrial appendages\",\n      \"pmids\": [\"9168779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlation does not separate cause from consequence of AF remodeling\", \"Mechanism of protein reduction not defined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Reconstituting Kvβ2.1/Kv1.5 and later Kvβ3.1/Kv1.5 co-assembly answered how auxiliary subunits tune Kv1.5 gating and inactivation.\",\n      \"evidence\": \"Cloning, immunopurification and patch-clamp of Kvβ2.1 (HEK293/L-cells) and Kvβ3.1 (CHO) co-expression\",\n      \"pmids\": [\"8576199\", \"9857044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Native stoichiometry of Kv1.5:Kvβ complexes in myocytes not determined\", \"Structural basis of inactivation shift not resolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identifying PKA phosphorylation of Kvβ1.3 Ser24 and intracellular ion-coupled slow inactivation revealed how Kv1.5 inactivation is dynamically controlled by signaling and permeation.\",\n      \"evidence\": \"Charge-swap mutagenesis with PKA modulation in oocytes/HEK293, and ion-substitution patch-clamp with gating currents\",\n      \"pmids\": [\"10318802\", \"10050000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether these gating effects operate at physiological signaling levels in atrial myocytes not addressed\", \"Slow inactivation mechanism shown to be non-classical but molecular pathway incomplete\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrating Src-family kinase association and tyrosine phosphorylation of Kv1.5 established kinase control of channel activity beyond Kvβ-mediated effects.\",\n      \"evidence\": \"Co-IP, antisense, PP2, constitutively active Src and patch-clamp in astrocytes\",\n      \"pmids\": [\"10884308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphorylation site on Kv1.5 not mapped in this study\", \"Relevance to cardiac Kv1.5 not tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identifying alpha-actinin-2 and SAP97 as anchoring partners answered how Kv1.5 is positioned and stabilized at the membrane.\",\n      \"evidence\": \"Yeast two-hybrid/in vitro binding mapping alpha-actinin-2 to Kv1.5 residues 73–148; co-IP, TDL motif mutagenesis and oocyte expression for SAP97\",\n      \"pmids\": [\"11389904\", \"11709425\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of alpha-actinin-2 binding not quantified in 2001\", \"SAP97 mechanism (PDZ-dependent vs indirect) not yet reconciled\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showing Kv1.2/Kv1.5 heterotetramers reproduce native vascular current established that Kv1.5 operates as a heteromeric channel in smooth muscle.\",\n      \"evidence\": \"Native vascular myocyte patch-clamp and tandem heterotetramer constructs in mammalian cells with pharmacology\",\n      \"pmids\": [\"11717161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Native subunit stoichiometry inferred from tandem constructs\", \"In vivo vascular role not yet established\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Resolving PKA/cytoskeleton-dependent current maintenance, PKC/Kvβ1.2-dependent suppression, and external H+/Zn2+ pore inhibition mapped how Kv1.5 integrates kinase, cytoskeletal and extracellular regulatory inputs.\",\n      \"evidence\": \"PKA/phosphatase and alpha-actinin-2 antisense in oocytes; PMA/PKC inhibitor co-expression in HEK293; H463Q/R487V mutagenesis with gating currents\",\n      \"pmids\": [\"11809852\", \"12130714\", \"12015417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of these parallel pathways in native myocytes not addressed\", \"Phosphatase identity in PKA maintenance not defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating SAP97 isoform-specific regulation and confirming Kv1.5 as the basis of canine atrial IKur clarified both anchoring control and the channel's identity as the IKur carrier.\",\n      \"evidence\": \"SAP97 isoform cloning, co-IP, imaging and patch-clamp; selective IKur blocker, RT-PCR, fractionation and AP recordings in canine atrial myocytes\",\n      \"pmids\": [\"12970345\", \"14500335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SAP97 physically binds Kv1.5 remained contested (see 12860415)\", \"Isoform balance in human disease not quantified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Reporting that SAP97 augments Kv1.5 current through an N-terminal, PDZ-independent and largely interaction-negative mechanism complicated the simple PDZ-anchoring model.\",\n      \"evidence\": \"N-/C-terminal deletion mutagenesis, yeast two-hybrid, co-IP and co-localization in HEK and myocytes, oocyte expression\",\n      \"pmids\": [\"12860415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physical interaction was largely undetectable, leaving the mechanism unresolved\", \"Reconciliation with PDZ-dependent co-IP data not achieved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying dynein/microtubule retrograde transport and proteasomal degradation answered how Kv1.5 surface levels are continuously opposed by removal and turnover pathways.\",\n      \"evidence\": \"p50/dynamitin, dynamin peptide, nocodazole, surface-accessibility and co-IP for dynein; pulse-chase with proteasome/lysosome inhibitors in COS and rat atrial cells\",\n      \"pmids\": [\"16051887\", \"16185660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating proteasomal targeting not identified in these studies\", \"Coupling between retrograde transport and degradation not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing Kv1.3/Kv1.5 heterotetramers in macrophages, 5-HT2A-driven internalization, and a dominant-negative AF truncation defined heteromeric assembly, receptor-triggered endocytosis, and the first disease mutation mechanism.\",\n      \"evidence\": \"FRET/co-IP heterotetramer assembly; 5-HT2A pharmacology and caveolar endocytosis in PASMC; E375X expression with dominant-negative testing, AP recordings and aminoglycoside rescue\",\n      \"pmids\": [\"17038323\", \"16527989\", \"16772329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution of receptor-driven internalization to disease not established\", \"Penetrance and frequency of E375X-type mutations not addressed by mechanism\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defining SUMOylation, S-acylation, Rab4/Rab11 recycling and cholesterol/caveolin-dependent trafficking built the core picture of how post-translational modification and endosomal sorting govern Kv1.5 surface density and gating.\",\n      \"evidence\": \"In vitro/in vivo SUMO assays with SENP2; hydroxylamine and cysteine mutagenesis for S-acylation; Rab4/Rab11 dominant-negative/constitutive mutants in HL-1; sucrose gradients and caveolin co-expression; methyl-β-cyclodextrin imaging in atrial myocytes\",\n      \"pmids\": [\"17261810\", \"17344312\", \"17673464\", \"18045854\", \"17525113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymes catalyzing Kv1.5 S-acylation not identified\", \"How these modifications are coordinated in vivo not resolved\", \"Caveolar dependence conflicts with negative caveolae findings (17054951)\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Characterizing FHL1 and the NADPH-sensitive C-terminal Kvβ interface, plus SAP97 immobilization, Kv1.3 microdomain effects, and post-endocytic Rab sorting, expanded the C-terminal interactome and refined the trafficking map.\",\n      \"evidence\": \"GST pull-down/MS and co-IP for FHL1; C-terminal deletion and nucleotide-infusion patch-clamp for Kvβ; FRAP/imaging for SAP97 and Kv1.3 heterotetramers; Rab5/Rab4/Rab7 mutants in H9c2\",\n      \"pmids\": [\"18281375\", \"22426702\", \"18245566\", \"18218624\", \"18755741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural model of the FHL1/Kv1.5 C-terminal complex not determined\", \"Physiological metabolic conditions sensed by NADPH-dependent Kvβ regulation not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Localizing cholesterol-regulated trafficking to the Rab11 recycling endosome answered which endosomal pool cholesterol controls to set Kv1.5 surface levels.\",\n      \"evidence\": \"Patch-clamp, single-channel, FRAP, co-IP and Rab11/Rab4 dominant-negatives in adult rat atrial myocytes\",\n      \"pmids\": [\"19706553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular cholesterol sensor controlling exocytosis not identified\", \"Link between membrane cholesterol and Rab11 machinery mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying redox sulfenic acid modification of Cys581, AMPK/Nedd4-2 downregulation, and the PKC-dependent Kv1.5/Kvβ1.3/RACK1 channelosome connected oxidative and metabolic stress signaling to Kv1.5 trafficking and inactivation.\",\n      \"evidence\": \"DAz sulfenic acid probe and C581 mutagenesis with human AF tissue; AMPK mutant panel and Nedd4-2 co-expression in oocytes; co-IP/siRNA/inhibitor dissection of the PKC channelosome in HEK and rat tissue\",\n      \"pmids\": [\"22843785\", \"23221389\", \"22547057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase coupling redox modification to degradation not pinpointed\", \"Whether AMPK acts through Nedd4-2 directly on Kv1.5 not proven\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Genetic rescue showing vascular smooth muscle Kv1.5 is required for H2O2-dependent coronary metabolic dilation, plus urate/ROS/ERK upregulation and KCNA5 promoter methylation in cancer, broadened Kv1.5 function into vascular physiology and disease beyond the atrium.\",\n      \"evidence\": \"Kv1.5-null mice with smooth-muscle-specific rescue and in vivo/ex vivo vasoreactivity; URATv1/ROS/ERK pharmacology in HL-1; promoter methylation and decitabine in Ewing sarcoma\",\n      \"pmids\": [\"26224794\", \"26477273\", \"26573141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between H2O2 sensing and Kv1.5 activation in smooth muscle not defined\", \"Role of KCNA5 silencing in tumor biology mechanistically thin\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Cataloguing gain- and loss-of-function KCNA5 mutations in lone atrial fibrillation strengthened the causal genetic link and tied current changes to surface expression defects.\",\n      \"evidence\": \"KCNA5 sequencing, confocal surface-expression and patch-clamp of multiple mutants in transfected cells\",\n      \"pmids\": [\"23264583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trafficking defects of loss-of-function mutants not mechanistically dissected\", \"In vivo arrhythmogenicity of individual variants not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many parallel regulatory inputs — Kvβ subunits, kinase channelosomes, SUMO/S-acylation, redox modification, and Rab/cholesterol/dynein trafficking — are integrated to set Kv1.5 surface density and gating in a given cell type, and which E3 ligase couples modification to degradation, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model integrating modification, anchoring and trafficking inputs\", \"Identity of the ubiquitin ligase targeting Kv1.5 not established\", \"Molecular H2O2 sensor for vascular Kv1.5 activation unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [2, 13, 1, 37]},\n      {\"term_id\": \"GO:0005216\", \"supporting_discovery_ids\": [2, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 16, 22, 31, 26]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [22, 27, 31]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [40, 23]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [16, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 13]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [16, 22, 27, 31]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [21, 23, 40, 33]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [19, 36, 2, 33]}\n    ],\n    \"complexes\": [\n      \"Kv1.5/Kvβ channel complex\",\n      \"Kv1.5/Kv1.3 heterotetramer\",\n      \"Kv1.5/Kv1.2 heterotetramer\",\n      \"Kv1.5/Kvβ1.3/RACK1/PKC channelosome\"\n    ],\n    \"partners\": [\n      \"KCNAB2\",\n      \"KCNAB3\",\n      \"KCNA3\",\n      \"KCNA2\",\n      \"DLG1\",\n      \"ACTN2\",\n      \"FHL1\",\n      \"RAB11A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}