{"gene":"KCNMA1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1991,"finding":"The Drosophila slo locus encodes a structural component of Ca2+-activated K+ channels; the predicted polypeptide shares similarity with voltage-activated K+ channel polypeptides in domains essential for function, and slo mutations specifically abolish Ca2+-activated K+ current in muscles and neurons.","method":"Genomic and cDNA cloning, sequencing, loss-of-function genetic analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — foundational molecular cloning combined with loss-of-function genetics in Drosophila; independently replicated in subsequent work across many labs","pmids":["1857984"],"is_preprint":false},{"year":1997,"finding":"A cysteine-rich 59-amino acid insert encoded by a novel alternative exon in the rat Slo gene (expressed in chromaffin cells, PC12 cells, pancreas, pituitary, cerebellum, hippocampus) confers a −20 to −30 mV shift in the conductance-voltage curve when expressed in Xenopus oocytes, demonstrating that alternative splicing at this site modulates BK channel voltage-dependence.","method":"cDNA library screening, Xenopus oocyte expression, electrophysiology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct functional measurement in heterologous expression system with defined splice variant construct; single lab but two orthogonal methods (cloning + electrophysiology)","pmids":["9115223"],"is_preprint":false},{"year":1998,"finding":"Co-expression of Slo (KCNMA1) with the related Slack subunit in oocytes generates intermediate-conductance channels (~60–180 pS) activated by cytoplasmic calcium, distinct from either Slack or Slo alone, demonstrating that Slack and Slo subunits physically interact to form heteromeric channels.","method":"Heterologous co-expression in oocytes, single-channel patch-clamp electrophysiology","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct electrophysiological reconstitution of heteromeric channel properties in co-expression system; single lab with rigorous single-channel characterization","pmids":["10196543"],"is_preprint":false},{"year":2002,"finding":"The alternatively spliced STREX exon (59 aa, cysteine-rich) in the cytoplasmic C-terminus of rat Slo (rSlo/KCNMA1) inverts regulation by cAMP-dependent protein kinase (PKA) from activation to inhibition, increases sensitivity to oxidation ~10-fold, and increases sensitivity to Ca2+ stimulation; these effects require co-assembly with β1 subunits and interact with N-terminal variation of the channel.","method":"Splice variant expression in pituitary cells (GH4C1), patch-clamp electrophysiology, PKA/PKG pharmacology, oxidation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal functional assays (PKA, PKG, oxidation, Ca2+ sensitivity) on defined splice variants in a single rigorous study","pmids":["12016222"],"is_preprint":false},{"year":2002,"finding":"Glucocorticoids directly applied to bovine adrenal chromaffin cells decreased STREX exon inclusion in Slo transcripts (effect blocked by glucocorticoid receptor antagonist RU38486), while adrenal androgens (DHEA, androstenedione, testosterone) increased STREX inclusion, demonstrating opposing steroid hormone regulation of Slo alternative splicing.","method":"In vitro cell culture of bovine chromaffin cells, RT-PCR quantification of splice variants, pharmacological receptor antagonist experiments","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean pharmacological dissection of receptor-mediated splicing regulation with specific antagonists in primary cells; single lab, two orthogonal approaches (hormone treatment + receptor antagonist)","pmids":["12032350"],"is_preprint":false},{"year":2003,"finding":"The slo core-linker domain (transmembrane core through the linker region) is a critical structural determinant of differential BKCa channel responses to ethanol; channels with an mslo-type core-linker are consistently activated by ethanol, while channels with a bslo-type core-linker display heterogeneous responses (inhibition, refractoriness, or activation).","method":"Chimeric channel construction (mslo/bslo), single-channel patch-clamp in cell-free membrane patches","journal":"Alcoholism, clinical and experimental research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — domain-swap chimera approach with single-channel electrophysiology in cell-free patches; single lab but rigorous mechanistic dissection","pmids":["14574235"],"is_preprint":false},{"year":2004,"finding":"In Drosophila, slo gene expression in the nervous system is induced by sedation with benzyl alcohol, and this induction is both necessary and sufficient for rapid drug tolerance: a mutation eliminating slo expression prevents tolerance, while transgenic induction of slo mimics tolerance in naive animals.","method":"Genetic loss-of-function mutation, inducible transgene expression, behavioral assay in Drosophila","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with both loss-of-function and gain-of-function (transgene) approaches converging on the same phenotype; rigorous behavioral assay","pmids":["15569939"],"is_preprint":false},{"year":2004,"finding":"In Aplysia bag cell neurons, a PKA-regulated splice isoform of slo (slo-a, containing a PKA consensus phosphorylation site) is expressed in adult but not juvenile neurons. PKA reduces open probability of Slo-a channels but has no effect on Slo-b (lacking the site), providing a mechanism for developmental regulation of neuronal excitability and reproductive afterdischarges.","method":"cDNA library isolation, CHO cell expression with patch-clamp, immunocytochemistry, PKA pharmacology, native neuron recordings","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro functional assay with defined isoforms plus PKA pharmacology and in vivo confirmation by immunocytochemistry; single lab, multiple orthogonal methods","pmids":["15375169"],"is_preprint":false},{"year":2005,"finding":"CaMKII phosphorylates Thr107 on the S0-S1 cytosolic loop of bovine Slo (BK channel); incremental phosphorylation of Thr107 progressively increases channel activity and converts alcohol responses from activation to inhibition, identifying this residue as a molecular switch regulating BK channel function and alcohol responses.","method":"Site-directed mutagenesis of Thr107, in vitro CaMKII phosphorylation assay, patch-clamp electrophysiology, ethanol exposure","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis combined with in vitro kinase assay and electrophysiology; single lab but multiple orthogonal methods establishing the phosphorylation-function link","pmids":["16341213"],"is_preprint":false},{"year":2005,"finding":"Estrogen progressively downregulates STREX exon inclusion in rat Slo transcripts during pregnancy (near 80% reduction at term), an effect blocked by estrogen receptor antagonist ICI 182,780 and opposed by progesterone, providing a mechanism for pregnancy-related switch in Slo PKA regulation from inhibitory (STREX present) to excitatory (STREX absent).","method":"RT-PCR quantification of splice variants during pregnancy, estrogen/progesterone/antagonist treatment of rats","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo pharmacological manipulation plus receptor antagonist with quantitative RT-PCR; single lab, two orthogonal approaches","pmids":["16102753"],"is_preprint":false},{"year":2007,"finding":"In C. elegans, slo-1 (encoding a Ca2+-activated K+ channel homologous to mammalian BK/KCNMA1) is required for the anthelmintic action of emodepside; nine alleles of slo-1 recovered in a mutagenesis screen confer high resistance, and tissue-specific rescue shows emodepside acts through SLO-1 in body wall muscle or neurons to inhibit locomotion, and in neurons (not muscle) via a latrophilin-facilitated pathway to inhibit feeding.","method":"Forward genetic screen, mutagenesis, tissue-specific genetic rescue, behavioral assays in C. elegans","journal":"International journal for parasitology","confidence":"High","confidence_rationale":"Tier 2 / Strong — forward genetic screen recovering multiple alleles, combined with tissue-specific rescue experiments; independently replicated across several subsequent studies","pmids":["17583712"],"is_preprint":false},{"year":2008,"finding":"In mouse distal colon, aldosterone-induced K+ secretion occurs exclusively via luminal KCa1.1 (BK) channels; high-K+ diet causes 2-fold increase in iberiotoxin-sensitive K+ secretion absent in BK alpha-subunit knockout (BK−/−) mice, demonstrating that aldosterone acts through increased BK channel expression to mediate colonic K+ secretion.","method":"Ussing chamber electrophysiology, BK knockout mice, pharmacological inhibition (iberiotoxin), immunohistochemistry, mRNA quantification","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (knockout, pharmacology, electrophysiology, IHC) in a well-controlled study; phenotype confirmed in genetic null animals","pmids":["18617563"],"is_preprint":false},{"year":2012,"finding":"In mouse submandibular exocrine gland, KCa1.1 channels localize to apical membranes of striated and excretory duct cells and mediate K+ secretion; K+ secretion is reduced >75% in KCa1.1 null mice and by the specific blocker paxilline, whereas KCa3.1 null mice show no change.","method":"KCa1.1 knockout mice, paxilline pharmacology, saliva ion measurement, immunohistochemistry, patch-clamp electrophysiology","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null combined with specific pharmacological blocker and direct localization by IHC; multiple orthogonal methods in a single rigorous study","pmids":["18216162"],"is_preprint":false},{"year":2011,"finding":"KCa1.1 (BK/KCNMA1) is the major potassium channel at the plasma membrane of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS); blocking this channel perturbs calcium homeostasis and inhibits RA-FLS proliferation, VEGF/IL-8/pro-MMP-2 production, and migration/invasion.","method":"Patch-clamp electrophysiology, siRNA knockdown, pharmacological channel blockade, proliferation and invasion assays, calcium imaging in primary RA-FLS","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown plus pharmacological blockade with multiple functional readouts in primary human cells; single lab, multiple orthogonal methods","pmids":["22074915"],"is_preprint":false},{"year":2012,"finding":"Single-molecule TIRF imaging in living VSMCs shows that BKα subunit mobility on the plasma membrane is restricted by its auxiliary β1 subunit (~50% reduction in diffusion coefficient), by the actin cytoskeleton (cytochalasin D increases mobility), and by direct interaction with caveolin-1 (Cav1; FRET confirmed co-localization), revealing that dynamic regulation of BKα membrane organization involves these three partners.","method":"Single-molecule TIRF microscopy, FRET, co-immunoprecipitation, cytoskeletal disruption pharmacology in HEK293 and VSMCs","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — single-molecule live imaging combined with FRET and Co-IP; single lab but multiple orthogonal biophysical methods","pmids":["22301058"],"is_preprint":false},{"year":2013,"finding":"MitoBKCa is encoded by the Kcnma1 gene and is targeted to mitochondria by a 50-amino acid C-terminal splice insert; purified cardiomyocyte mitochondria contain a ~140 kDa Kcnma1-derived protein arranged in ~50 nm clusters, and NS1619-mediated cardioprotection is absent in Kcnma1 knockout mice, establishing KCNMA1 as the molecular correlate of mitoBKCa.","method":"Biochemical fractionation, Western blotting, electron microscopy of purified mitochondria, Kcnma1 knockout mice, in vivo cardioprotection assay, BK transcript analysis","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (fractionation, EM, genetic knockout ablating cardioprotection, discovery of targeting splice insert); replicated concept by subsequent study","pmids":["23754429"],"is_preprint":false},{"year":2013,"finding":"Cav3 (T-type) calcium channels physically associate with the transmembrane S0 segment of KCa1.1 (BKα N-terminus) via co-immunoprecipitation from both transfected cells and rat brain; this Cav3-KCa1.1 complex enables Cav3 calcium influx to shift KCa1.1 voltage for activation ~50 mV negative, activating KCa1.1 at low voltages matching the T-type Ca2+ channel profile.","method":"Co-immunoprecipitation from brain and transfected tsA-201 cells, patch-clamp electrophysiology with pharmacological blockers and pore-dead Cav3 mutant, native neuron recordings (medial vestibular neurons)","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP from brain tissue plus reconstitution in cells with mutagenesis (pore mutant Cav3) and pharmacological dissection; native neuron confirmation","pmids":["23626738"],"is_preprint":false},{"year":2013,"finding":"TRPV1 channels are functionally coupled with BK (mSlo1/KCNMA1) channels in rat DRG neurons; Ca2+ influx through TRPV1 activates BK channels within submilliseconds (estimated local Ca2+ >10 µM around BK), an effect blocked by 10 mM BAPTA but not 5 mM EGTA, and TRPV1-BK complex formation was confirmed by co-immunoprecipitation and fluorescence co-localization.","method":"Patch-clamp electrophysiology (infrared laser TRPV1 activation), co-immunoprecipitation, fluorescence imaging in HEK cells and native DRG neurons","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — functional coupling demonstrated by fast Ca2+ chelator differential and Co-IP; single lab with multiple orthogonal methods","pmids":["24147119"],"is_preprint":false},{"year":2014,"finding":"BK channels encoded by KCNMA1 are present in cardiomyocyte mitochondria (mitoplast electrophysiology confirms paxilline- and NS11021-sensitive 190 pS conductance absent in BK−/− mice); BK−/− cardiomyocytes show attenuated oxidative phosphorylation capacity, elevated post-anoxic ROS, and enlarged infarcts upon ischemic pre-conditioning (IP), while infarcts without IP are unchanged, establishing that KCNMA1-encoded mitoBK mediates the beneficial effects of IP partly through modulation of mitochondrial ROS.","method":"Mitoplast electrophysiology, BK knockout mice, ex vivo ischemia/reperfusion model, mitochondrial ROS and respiration measurements, electron microscopy","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — electrophysiological confirmation in knockout mitoplasts plus multiple functional readouts (respiration, ROS, infarct area) across genetic null animals; multiple orthogonal methods","pmids":["25072914"],"is_preprint":false},{"year":2014,"finding":"Emodepside directly opens C. elegans Slo-1a channels expressed in Xenopus oocytes (1–10 µM emodepside increased currents across a wide range of step potentials in the absence of experimentally increased intracellular Ca2+), and the effect is irreversible upon washout; the Slo-1 inhibitor verruculogen was only effective when applied before, not after, emodepside, indicating a stable drug-channel interaction.","method":"Heterologous expression of C. elegans Slo-1a in Xenopus oocytes, voltage-clamp electrophysiology, pharmacological washout and competition experiments","journal":"PLoS neglected tropical diseases","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro electrophysiological reconstitution of emodepside action on isolated channel; pharmacological competition establishes binding mechanism; single lab but rigorous voltage-clamp study","pmids":["25521608"],"is_preprint":false},{"year":2014,"finding":"11,12-EET induces smooth muscle hyperpolarization and vascular relaxation in human internal mammary arteries through a TRPV4-TRPC1-KCa1.1 ternary complex; co-immunoprecipitation shows TRPV4, TRPC1, and KCa1.1 physically interact, and TRPC1 is the linker enabling TRPV4-KCa1.1α interaction.","method":"Co-immunoprecipitation in human LIMA tissue and HEK293 cells, microelectrode membrane potential recordings, vascular tension assays, siRNA/pharmacological suppression of each component","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP from native tissue plus functional validation in HEK293 cells with domain-specific loss-of-function; single lab, multiple orthogonal methods","pmids":["25511389"],"is_preprint":false},{"year":2015,"finding":"Human KCNMA1 expressed in C. elegans slo-1 null mutants rescues behavioral deficits of loss of slo-1 signaling, but worms expressing human KCNMA1 are 10–100-fold less sensitive to emodepside than those expressing the nematode channel, demonstrating species-selective pharmacological differences in the emodepside-SLO1 interaction and predicting an emodepside pharmacophore in nematode SLO-1.","method":"Transgenic expression of human KCNMA1 in C. elegans slo-1 null mutants, behavioral dose-response assays, pharmacological agonist testing","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 2 / Strong — humanized C. elegans rescue genetics with rigorous behavioral pharmacology; replicated in concept by subsequent cross-phyla electrophysiology study","pmids":["21415309"],"is_preprint":false},{"year":2015,"finding":"Emodepside differentially modulates human KCNMA1 versus nematode Slo-1 and insect Drosophila Slo in whole-cell voltage clamp: nematode SLO-1 is strongly facilitated (+73%) at 100 nM; human KCNMA1 shows transient facilitation (+33.5%) followed by sustained inhibition (−52.6%) at 100 nM; insect Slo is activated at low Ca2+ but inhibited at higher Ca2+, establishing species-specific pharmacodynamics.","method":"Heterologous expression of orthologous SLO channels in voltage-clamp whole-cell recordings, cross-phyla comparison","journal":"PLoS neglected tropical diseases","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro electrophysiological comparison of three orthologous channels under identical conditions; single lab but rigorous quantitative voltage-clamp","pmids":["26437177"],"is_preprint":false},{"year":2016,"finding":"KCa1.1 channels regulate human skeletal myoblast proliferation, migration, and fusion; blocking KCa1.1 function increases cytosolic Ca2+ and NFκB levels, enhances proliferation, and decreases MMP secretion, migration, and myotube fusion, phenocopying DM1 myoblasts; DM1 myoblasts show loss of plasma membrane expression of KCa1.1 α-subunit, and reintroducing functional KCa1.1 α-subunits into DM1 myoblasts normalizes proliferation and rescues Mef2 expression.","method":"Patch-clamp electrophysiology, siRNA knockdown, KCa1.1 α-subunit overexpression rescue, Ca2+ imaging, NFκB assay, proliferation/migration/fusion assays in primary human myoblasts","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function rescue in primary human cells with multiple cellular readouts; single lab with multiple orthogonal methods","pmids":["27763639"],"is_preprint":false},{"year":2017,"finding":"KCa1.1 (KCNMA1) α-subunit co-immunoprecipitates with β1 integrins in RA-FLS; blocking KCa1.1 disturbs calcium homeostasis, causes sustained Akt phosphorylation and talin recruitment to β1 integrins, and reduces RA-FLS adhesion, migration, and invasion through β1 integrin regulation—but not via α4, α5, or α6 integrins.","method":"Co-immunoprecipitation, patch-clamp, Ca2+ imaging, Akt phosphorylation assay, flow cytometry for integrin activation, functional invasion/adhesion assays in human RA-FLS","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating physical association plus mechanistic signaling cascade (Ca2+/Akt/talin/β1-integrin) with multiple functional readouts; single lab, multiple orthogonal methods","pmids":["28428266"],"is_preprint":false},{"year":2012,"finding":"Loss-of-function mutation of TMPRSS3 (type II serine protease) in mice impairs outward K+ currents in cochlear inner hair cells (IHCs) and causes absence of KCNMA1 (BK channel) protein at the neck of IHCs, demonstrating that TMPRSS3 is required for proper Kcnma1 channel membrane expression in IHCs.","method":"Patch-clamp electrophysiology in Tmprss3 mutant mice, proteomic analysis, immunohistochemistry","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse model with electrophysiology and proteomic/IHC confirmation; single lab, two orthogonal methods, but mechanistic link between TMPRSS3 activity and Kcnma1 trafficking not biochemically resolved","pmids":["23255163"],"is_preprint":false},{"year":2019,"finding":"KCNMA1 mutations identified in patients with gain-of-function (GOF) biophysical properties (e.g. D434G, N999S) cause paroxysmal non-kinesigenic dyskinesia and epilepsy (PNKD3), while loss-of-function (LOF) variants are associated with distinct neurological phenotypes including ataxia and developmental delay, establishing a genotype-phenotype correlation for KCNMA1-linked channelopathy.","method":"Patch-clamp electrophysiology of patient mutations expressed in HEK cells, exome/genome sequencing of patient cohort","journal":"The Journal of general physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiological functional characterization of multiple patient alleles; compiled from multiple independent cases but pharmacological mechanisms not fully dissected","pmids":["31427379"],"is_preprint":false},{"year":2019,"finding":"Eight novel KCNMA1 loss-of-function variants (e.g. Ser351Tyr, Gly356Arg, Gly375Arg, Ile663Val abolish BK current; Cys413Tyr and Pro805Leu reduce amplitude and shift activation to positive potentials; Asp984Asn reduces amplitude without affecting kinetics) cause a new neurodevelopmental syndrome (Liang-Wang syndrome) characterized by developmental delay, visceral/cardiac malformations, and neurological symptoms.","method":"Exome/genome sequencing, patch-clamp electrophysiology of mutant BK channels in heterologous cells","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct patch-clamp characterization of eight individual patient mutations with defined loss-of-function mechanisms; single study but rigorous electrophysiology on multiple variants","pmids":["31152168"],"is_preprint":false},{"year":2020,"finding":"The KCNMA1-N536H de novo mutation produces a gain-of-function BK channel with markedly enhanced voltage-dependent activation; dextroamphetamine treatment completely suppressed dystonia-atonia spells in the affected patient, identifying a functional mechanism and a treatment approach.","method":"Patch-clamp electrophysiology of N536H BK channel in heterologous cells, clinical treatment response","journal":"Movement disorders","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous patch-clamp characterization of mutation in single study; clinical treatment is a single patient case report","pmids":["32633875"],"is_preprint":false},{"year":2022,"finding":"Three KCNMA1 patient variants show distinct BK channel properties: N999S and D434G are gain-of-function (GOF; BKN999S > BKD434G > WT in activity), while H444Q is loss-of-function (LOF). Knockin mice for N999S and D434G show increased BK currents, broadened action potentials, decreased seizure thresholds, and paroxysmal dyskinesia-like immobility after stress; H444Q/WT mice lack these phenotypes, establishing relative pathogenic severity N999S > D434G > H444Q.","method":"Heterologous patch-clamp, transgenic knockin mice, in vivo seizure threshold, behavioral dyskinesia assay, dextroamphetamine treatment","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple knockin mouse models with electrophysiology, behavioral, and pharmacological characterization; cross-allele comparison in same genetic background","pmids":["35819138"],"is_preprint":false},{"year":2022,"finding":"Two new de novo KCNMA1 loss-of-function variants p.(A172T) and p.(A314T) associated with Liang-Wang syndrome: p.(A172T) abolishes BK current and inhibits Mg2+-dependent gating while shifting G-V curves to positive potentials when co-expressed with WT; p.(A314T) suppresses current amplitude and shifts G-V curves positive with WT. Both variants reduce total and membrane BK protein levels.","method":"Patch-clamp electrophysiology in heterologous cells, Western blotting for total and membrane protein","journal":"Acta physiologica","confidence":"High","confidence_rationale":"Tier 1 / Moderate — patch-clamp characterization of defined mutations with parallel biochemical quantification of channel protein levels; single lab, two orthogonal methods","pmids":["35156297"],"is_preprint":false},{"year":2020,"finding":"The transcription factor Nrf2 directly binds to the antioxidant response element (ARE) of the KCNMA1 promoter (confirmed by luciferase reporter assay) and transcriptionally upregulates BKα (KCNMA1) expression; Nrf2 knockout mice show reduced BKα mRNA and protein in coronary arteries and diminished BK channel current density, whereas adenoviral Nrf2 expression increases BKα protein and BK channel activity in coronary arterial smooth muscle cells.","method":"Promoter-luciferase reporter assay, Nrf2 knockout mice, adenoviral overexpression, patch-clamp electrophysiology, Western blotting, qPCR","journal":"Journal of molecular and cellular cardiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct promoter binding assay plus genetic knockout and rescue with multiple orthogonal methods; single lab but comprehensive mechanistic dissection","pmids":["32147517"],"is_preprint":false},{"year":2012,"finding":"In human UBSM, PDE inhibition causes ~3.6-fold increase in transient KCa1.1 channel current frequency and membrane hyperpolarization (~5.6 mV); paxilline (KCa1.1 blocker) abolishes spontaneous transient hyperpolarization and the PDE inhibitor-induced hyperpolarization, and eliminates PDE-blocker-induced relaxation of both spontaneous and nerve-evoked contractions, establishing KCa1.1 as the critical effector of cAMP-mediated UBSM relaxation.","method":"Patch-clamp electrophysiology, live-cell Ca2+ imaging, isometric tension recording in human UBSM strips, pharmacological blockade with paxilline","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — convergent electrophysiology and contractility data in human tissue with specific pharmacological blockade; single lab, multiple orthogonal methods","pmids":["22896041"],"is_preprint":false},{"year":2006,"finding":"In C. elegans, SLO-1 co-localizes with dystrophin homologue DYS-1 in muscle M-lines and dense bodies (Z-lines) by GFP reporter; inactivation of slo-1 in muscles causes progressive degeneration in sensitized backgrounds similar to dys-1 mutations, and single-channel recordings confirm the Ca2+-activated K+ channel in body-wall muscle is SLO-1; channel abundance and conductance are unchanged in dys-1 mutants, suggesting DYS-1 regulates SLO-1 activity rather than expression.","method":"GFP reporter localization, genetic epistasis in C. elegans, inside-out patch-clamp electrophysiology of body-wall muscle cells","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct single-channel electrophysiology combined with subcellular localization imaging and genetic epistasis; single lab, multiple orthogonal methods","pmids":["16527307"],"is_preprint":false},{"year":2016,"finding":"In C. elegans AWC olfactory neuron differentiation, SLO-1 BK channels act downstream of NSY-5 gap junctions to inhibit voltage-activated calcium channel signaling (UNC-2/CaV2 and EGL-19/CaV1), specifying AWCON identity; nsy-5-dependent asymmetric expression of slo-1 in AWCON is necessary and sufficient for AWC asymmetry; SLO-1 co-localizes with UNC-2 and EGL-19 in AWC, and the auxiliary subunit BKIP-1 is required for SLO-1 and SLO-2 function in this context.","method":"Genetic epistasis in C. elegans, tissue-specific rescue, fluorescent localization, GFP reporter analysis","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic epistasis with multiple alleles, tissue-specific rescue, and co-localization; single lab but comprehensive epistatic analysis","pmids":["26771544"],"is_preprint":false},{"year":2005,"finding":"EGF receptor (EGFR) activation in native contractile rat basilar artery smooth muscle cells activates iberiotoxin-sensitive KCa1.1 (maxi-K) channels via an adenylate cyclase type 5 (AC-5)/cAMP-dependent protein kinase (PKA) pathway; EGFR-mediated KCa1.1 activation leads to membrane hyperpolarization and is required for PCNA upregulation, implicating KCa1.1 in EGFR-mediated proliferative signaling.","method":"Patch-clamp electrophysiology in freshly isolated VSMCs, antisense knockdown of EGFR and AC-5, PKA inhibitors, in vivo PCNA immunostaining","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology with pharmacological and antisense-mediated dissection of signaling pathway; single lab, multiple orthogonal approaches","pmids":["16284070"],"is_preprint":false},{"year":2010,"finding":"Chick β4-subunit increases Slo (BKα) responsiveness to physiological Ca2+ concentrations at hair cell operating voltages (around −50 mV), while both β4 and β1 subunits reduce Slo surface expression; β4 and β1 are preferentially expressed in low-frequency hair cells, providing a molecular basis for electrical tuning in these cells.","method":"Cloning of chick β4 and β1 subunits, heterologous expression in oocytes/cells with BKα, electrophysiology, surface expression quantification","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct electrophysiological reconstitution with defined subunit combinations; single lab, multiple functional readouts","pmids":["21178105"],"is_preprint":false},{"year":2016,"finding":"In C. elegans, alternative splicing at all three splice sites of slo-1 is coordinated; a point mutation in an intron adjacent to one alternate splice site disrupts coordination at all three sites and causes aberrant neuromuscular junction transmission; a UAAAUC intronic element disrupted by this mutation is enriched in genes with multiple alternate splice sites and appears to act as a cis-regulatory element for intragenic splicing coordination.","method":"Quantitative PCR-based splice variant quantification, conditional probability modeling, forward genetics in C. elegans, electrophysiological analysis of NMJ function","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — combination of quantitative splicing analysis, genetic point mutation, and NMJ electrophysiology; single lab","pmids":["22084100"],"is_preprint":false}],"current_model":"KCNMA1 encodes the pore-forming α-subunit of the large-conductance, Ca2+- and voltage-activated BK potassium channel, a homotetramer that contains a unique extracellular S0 segment and a large C-terminal cytoplasmic domain harboring multiple ligand-sensing (Ca2+, Mg2+) and regulatory domains; channel gating is positively regulated by membrane depolarization and intracellular Ca2+ (supplied locally by Cav1.2, Cav3, TRPV1, or TRPV4-TRPC1 complexes), is modulated by CaMKII phosphorylation of Thr107 and PKA-dependent phosphorylation of STREX-containing splice isoforms, and is subject to extensive tissue-specific alternative splicing (notably the STREX exon whose inclusion is regulated by glucocorticoids, androgens, estrogen/progesterone, and stress) that inverts PKA regulation and tunes Ca2+/oxidation sensitivity; the channel is transcriptionally regulated by Nrf2 and epigenetically silenced by promoter methylation in some cancers; a specific C-terminal splice insert targets a subpopulation of KCNMA1-encoded channels to cardiac mitochondria (mitoBKCa), where they fine-tune oxidative metabolism and mediate ischemic preconditioning; at the plasma membrane BKα mobility is restricted by its auxiliary β1 subunit, the actin cytoskeleton, and caveolin-1, and functionally it couples to β1-integrins to regulate cell invasiveness; gain-of-function mutations (notably N999S and D434G) cause paroxysmal non-kinesigenic dyskinesia and epilepsy, while loss-of-function mutations cause Liang-Wang syndrome with developmental delay and structural brain abnormalities."},"narrative":{"mechanistic_narrative":"KCNMA1 encodes the pore-forming α-subunit of the large-conductance Ca2+- and voltage-activated BK (KCa1.1) potassium channel, originally defined through the Drosophila slo locus whose mutations abolish Ca2+-activated K+ current in muscle and neurons [PMID:1857984]. Channel output is set by the convergence of membrane depolarization and intracellular Ca2+, which is supplied locally through physical association of BKα with partner Ca2+ sources: the S0 segment binds Cav3 to shift BK voltage-dependence ~50 mV negative [PMID:23626738], and BK forms co-immunoprecipitating complexes with TRPV1 [PMID:24147119] and a TRPV4-TRPC1 module [PMID:25511389] that deliver high local Ca2+ for rapid activation. The large cytoplasmic C-terminus and S0-S1 loop integrate post-translational and splicing inputs: CaMKII phosphorylation of Thr107 graded-tunes activity and inverts ethanol responses [PMID:16341213], the cysteine-rich STREX splice insert reverses PKA regulation from activation to inhibition and amplifies oxidation and Ca2+ sensitivity [PMID:12016222], and STREX inclusion is itself controlled by opposing steroid hormones—glucocorticoids versus androgens [PMID:12032350] and estrogen versus progesterone [PMID:16102753]. KCNMA1 channels also assemble as heteromers with related Slack subunits [PMID:10196543] and are modulated by auxiliary β1/β4 subunits that alter Ca2+ sensitivity and surface expression [PMID:21178105]. At the plasma membrane BKα mobility is restricted by the β1 subunit, the actin cytoskeleton, and caveolin-1 [PMID:22301058], and the channel couples to β1-integrins to control adhesion and invasion [PMID:28428266]. Functionally, BK mediates K+ secretion in colonic and salivary epithelia [PMID:18617563, PMID:18216162], smooth-muscle relaxation downstream of cAMP and EGFR signaling [PMID:22896041, PMID:16284070], and proliferation/migration in synoviocytes and myoblasts [PMID:22074915, PMID:27763639]; transcription is driven by Nrf2 binding the KCNMA1 promoter ARE [PMID:32147517]. A distinct C-terminal splice insert targets a population of KCNMA1-encoded channels to cardiac mitochondria, where mitoBKCa modulates oxidative metabolism, ROS, and ischemic preconditioning [PMID:23754429, PMID:25072914]. Gain-of-function variants (N999S, D434G) cause paroxysmal non-kinesigenic dyskinesia and epilepsy, while loss-of-function variants cause Liang-Wang syndrome with developmental delay and structural malformations [PMID:31427379, PMID:31152168, PMID:35819138].","teleology":[{"year":1991,"claim":"Established the molecular identity of the Ca2+-activated K+ channel by cloning the Drosophila slo locus, defining the founding gene of the BK family and linking it structurally to voltage-gated K+ channels.","evidence":"Genomic/cDNA cloning and loss-of-function genetics in Drosophila","pmids":["1857984"],"confidence":"High","gaps":["Mammalian KCNMA1 ortholog function not yet addressed","Ca2+-sensing and voltage-sensing domains not yet mapped"]},{"year":1997,"claim":"Showed that alternative splicing of the cytoplasmic region tunes BK voltage-dependence, revealing splicing as a primary mechanism for tissue-specific channel diversity.","evidence":"cDNA cloning of a 59-aa insert, Xenopus oocyte expression and electrophysiology","pmids":["9115223"],"confidence":"High","gaps":["Physiological trigger for inclusion not defined","Effect on Ca2+ sensitivity not addressed here"]},{"year":1998,"claim":"Demonstrated that Slo physically heteromerizes with the related Slack subunit, expanding the channel-output repertoire beyond homotetramers.","evidence":"Co-expression in oocytes with single-channel patch-clamp","pmids":["10196543"],"confidence":"High","gaps":["Native existence and stoichiometry of heteromers not established","Subunit interface not mapped"]},{"year":2002,"claim":"Defined the STREX splice insert as a regulatory switch that inverts PKA control and amplifies oxidation/Ca2+ sensitivity, and showed steroid hormones bidirectionally control its inclusion—linking splicing to endocrine and stress signaling.","evidence":"Splice-variant electrophysiology with PKA/oxidation assays; RT-PCR with receptor antagonists in chromaffin cells","pmids":["12016222","12032350"],"confidence":"High","gaps":["Splicing factors mediating hormone effects not identified","STREX cysteine oxidation chemistry not resolved"]},{"year":2005,"claim":"Identified Thr107 in the S0-S1 loop as a CaMKII-phosphorylated molecular switch grading channel activity and reversing ethanol responses, and showed PKA-regulated splice isoforms tune neuronal excitability developmentally.","evidence":"Site-directed mutagenesis, in vitro CaMKII assay, electrophysiology; Aplysia isoform recordings","pmids":["16341213","15375169"],"confidence":"High","gaps":["In vivo stoichiometry of Thr107 phosphorylation not quantified","Cross-talk between phosphorylation and splice state incompletely defined"]},{"year":2006,"claim":"Connected BK to cytoskeletal/dystrophin scaffolds in muscle, showing localization to M-lines and Z-lines and a protective role whose disruption mimics dystrophic degeneration.","evidence":"GFP localization, genetic epistasis, and single-channel patch-clamp in C. elegans muscle","pmids":["16527307"],"confidence":"High","gaps":["Mechanism by which DYS-1 regulates channel activity not biochemically defined","Relevance to mammalian muscle not tested here"]},{"year":2008,"claim":"Established BK as the obligatory effector of hormone-driven epithelial K+ secretion, demonstrating physiological transport roles in vivo.","evidence":"Ussing chamber electrophysiology, BK knockout mice, iberiotoxin, IHC in colon; later salivary gland knockout study","pmids":["18617563","18216162"],"confidence":"High","gaps":["Upstream regulation of BK expression by aldosterone not molecularly resolved","Coupling to apical Na+/Cl- transport incompletely defined"]},{"year":2012,"claim":"Showed BK membrane organization is dynamically constrained by the β1 subunit, actin, and caveolin-1, and that BK drives proliferation/invasion in pathological fibroblasts and smooth muscle relaxation downstream of cAMP—extending the channel into structural and proliferative cell biology.","evidence":"Single-molecule TIRF/FRET/Co-IP in VSMCs; siRNA and pharmacology in RA-FLS; patch-clamp and tension recording in human UBSM","pmids":["22301058","22074915","22896041"],"confidence":"High","gaps":["Caveolin-1 binding interface not mapped","Causal sequence linking Ca2+ homeostasis to proliferation incompletely resolved"]},{"year":2013,"claim":"Identified a C-terminal splice insert that targets KCNMA1 channels to cardiac mitochondria (mitoBKCa) and physical complexes with Cav3, TRPV1, and TRPV4-TRPC1 that supply local Ca2+—establishing both organellar targeting and source-channel coupling.","evidence":"Mitochondrial fractionation/EM and knockout cardioprotection; reciprocal Co-IP and reconstitution electrophysiology for Cav3/TRPV1/TRPV4-TRPC1","pmids":["23754429","23626738","24147119"],"confidence":"High","gaps":["MitoBKCa pore topology and import pathway not resolved","Stoichiometry of source-channel nanodomains not quantified"]},{"year":2014,"claim":"Functionally confirmed mitoBK by mitoplast electrophysiology and showed it mediates ischemic preconditioning via ROS modulation, defining a metabolic/cardioprotective role distinct from the plasma-membrane channel.","evidence":"Mitoplast patch-clamp, BK knockout mice, ex vivo ischemia/reperfusion, ROS/respiration measurements","pmids":["25072914"],"confidence":"High","gaps":["Mechanistic link between mitoBK K+ flux and ROS not fully defined","Channel partners within mitochondria unknown"]},{"year":2016,"claim":"Demonstrated BK regulation of myoblast proliferation/migration/fusion and rescue of disease phenotypes, broadening its role to muscle regeneration and differentiation.","evidence":"Patch-clamp, siRNA, α-subunit overexpression rescue, and cellular assays in primary human myoblasts","pmids":["27763639"],"confidence":"High","gaps":["Mechanism of membrane expression loss in DM1 not resolved","Link between BK and Mef2 transcription not defined"]},{"year":2017,"claim":"Showed BKα physically associates with β1-integrins and controls a Ca2+/Akt/talin axis governing adhesion and invasion, linking channel activity to integrin signaling specifically.","evidence":"Co-IP, patch-clamp, Ca2+ imaging, Akt/talin assays, and invasion assays in RA-FLS","pmids":["28428266"],"confidence":"High","gaps":["Direct vs scaffolded BK-integrin interaction not distinguished","Generality beyond RA-FLS not tested"]},{"year":2020,"claim":"Established Nrf2 as a direct transcriptional activator of KCNMA1 via the promoter ARE, linking the channel to oxidative-stress gene programs in vascular smooth muscle.","evidence":"Promoter-luciferase, Nrf2 knockout mice, adenoviral overexpression, patch-clamp","pmids":["32147517"],"confidence":"High","gaps":["Other transcriptional regulators not surveyed","Tissue specificity of Nrf2 control not defined"]},{"year":2022,"claim":"Resolved the genotype-phenotype architecture of KCNMA1 channelopathy by characterizing gain- and loss-of-function patient variants in cells and knockin mice and linking GOF to dyskinesia/epilepsy and LOF to Liang-Wang syndrome, with a candidate pharmacological intervention.","evidence":"Patch-clamp of patient variants, knockin mouse seizure/behavior assays, Western blot of channel levels, dextroamphetamine treatment","pmids":["31427379","31152168","32633875","35819138","35156297"],"confidence":"High","gaps":["Mechanism translating channel GOF to network hyperexcitability incompletely defined","Genotype-treatment matching for LOF patients unestablished"]},{"year":null,"claim":"How splice-state, phosphorylation, subunit composition, and partner-channel complexes are integrated in vivo to set BK output in specific tissues, and how this integration is perturbed across the spectrum of disease variants, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model coupling splicing, phosphorylation, and nanodomain assembly","Structural basis of variant pathogenicity incomplete","MitoBK targeting/import mechanism unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,2,11,12,18]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[31]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[16,17,20]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[13,14,24]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[15,18]}],"pathway":[],"complexes":["BK channel (KCNMA1/Slo-Slack heteromer)","Cav3-KCa1.1 complex","TRPV4-TRPC1-KCa1.1 ternary complex","mitoBKCa"],"partners":["KCNT1","CACNA1G","TRPV1","TRPV4","TRPC1","CAV1","ITGB1","NFE2L2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q12791","full_name":"Calcium-activated potassium channel subunit alpha-1","aliases":["BK channel","BKCA alpha","Calcium-activated potassium channel, subfamily M subunit alpha-1","K(VCA)alpha","KCa1.1","Maxi K channel","MaxiK","Slo-alpha","Slo1","Slowpoke homolog","Slo homolog","hSlo"],"length_aa":1236,"mass_kda":137.6,"function":"Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+) (PubMed:14523450, PubMed:29330545, PubMed:31152168). It is also activated by the concentration of cytosolic Mg(2+). Its activation dampens the excitatory events that elevate the cytosolic Ca(2+) concentration and/or depolarize the cell membrane. It therefore contributes to repolarization of the membrane potential. Plays a key role in controlling excitability in a number of systems, such as regulation of the contraction of smooth muscle, the tuning of hair cells in the cochlea, regulation of transmitter release, and innate immunity. In smooth muscles, its activation by high level of Ca(2+), caused by ryanodine receptors in the sarcoplasmic reticulum, regulates the membrane potential. In cochlea cells, its number and kinetic properties partly determine the characteristic frequency of each hair cell and thereby helps to establish a tonotopic map. Kinetics of KCNMA1 channels are determined by alternative splicing, phosphorylation status and its combination with modulating beta subunits. Highly sensitive to both iberiotoxin (IbTx) and charybdotoxin (CTX). Possibly induces sleep when activated by melatonin and through melatonin receptor MTNR1A-dependent dissociation of G-beta and G-gamma subunits, leading to increased sensitivity to Ca(2+) and reduced synaptic transmission (PubMed:32958651) Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q12791/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KCNMA1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KCNMA1","total_profiled":1310},"omim":[{"mim_id":"618729","title":"LIANG-WANG SYNDROME; LIWAS","url":"https://www.omim.org/entry/618729"},{"mim_id":"618596","title":"EPILEPSY, IDIOPATHIC GENERALIZED, SUSCEPTIBILITY TO, 16; EIG16","url":"https://www.omim.org/entry/618596"},{"mim_id":"617643","title":"CEREBELLAR ATROPHY, DEVELOPMENTAL DELAY, AND SEIZURES; CADEDS","url":"https://www.omim.org/entry/617643"},{"mim_id":"615215","title":"POTASSIUM CHANNEL, SUBFAMILY U, MEMBER 1; KCNU1","url":"https://www.omim.org/entry/615215"},{"mim_id":"613505","title":"LEUCINE-RICH REPEAT-CONTAINING PROTEIN 26; LRRC26","url":"https://www.omim.org/entry/613505"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KCNMA1"},"hgnc":{"alias_symbol":["KCa1.1","mSLO1"],"prev_symbol":["SLO"]},"alphafold":{"accession":"Q12791","domains":[{"cath_id":"-","chopping":"160-386","consensus_level":"medium","plddt":91.1198,"start":160,"end":386},{"cath_id":"3.30.70","chopping":"1099-1182","consensus_level":"medium","plddt":89.5504,"start":1099,"end":1182}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12791","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12791-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12791-F1-predicted_aligned_error_v6.png","plddt_mean":76.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KCNMA1","jax_strain_url":"https://www.jax.org/strain/search?query=KCNMA1"},"sequence":{"accession":"Q12791","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12791.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12791/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12791"}},"corpus_meta":[{"pmid":"1857984","id":"PMC_1857984","title":"A component of calcium-activated potassium channels encoded by the Drosophila slo locus.","date":"1991","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/1857984","citation_count":550,"is_preprint":false},{"pmid":"17115074","id":"PMC_17115074","title":"High-conductance potassium channels of the SLO family.","date":"2006","source":"Nature reviews. 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independently replicated in subsequent work across many labs\",\n      \"pmids\": [\"1857984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"A cysteine-rich 59-amino acid insert encoded by a novel alternative exon in the rat Slo gene (expressed in chromaffin cells, PC12 cells, pancreas, pituitary, cerebellum, hippocampus) confers a −20 to −30 mV shift in the conductance-voltage curve when expressed in Xenopus oocytes, demonstrating that alternative splicing at this site modulates BK channel voltage-dependence.\",\n      \"method\": \"cDNA library screening, Xenopus oocyte expression, electrophysiology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct functional measurement in heterologous expression system with defined splice variant construct; single lab but two orthogonal methods (cloning + electrophysiology)\",\n      \"pmids\": [\"9115223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Co-expression of Slo (KCNMA1) with the related Slack subunit in oocytes generates intermediate-conductance channels (~60–180 pS) activated by cytoplasmic calcium, distinct from either Slack or Slo alone, demonstrating that Slack and Slo subunits physically interact to form heteromeric channels.\",\n      \"method\": \"Heterologous co-expression in oocytes, single-channel patch-clamp electrophysiology\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct electrophysiological reconstitution of heteromeric channel properties in co-expression system; single lab with rigorous single-channel characterization\",\n      \"pmids\": [\"10196543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The alternatively spliced STREX exon (59 aa, cysteine-rich) in the cytoplasmic C-terminus of rat Slo (rSlo/KCNMA1) inverts regulation by cAMP-dependent protein kinase (PKA) from activation to inhibition, increases sensitivity to oxidation ~10-fold, and increases sensitivity to Ca2+ stimulation; these effects require co-assembly with β1 subunits and interact with N-terminal variation of the channel.\",\n      \"method\": \"Splice variant expression in pituitary cells (GH4C1), patch-clamp electrophysiology, PKA/PKG pharmacology, oxidation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal functional assays (PKA, PKG, oxidation, Ca2+ sensitivity) on defined splice variants in a single rigorous study\",\n      \"pmids\": [\"12016222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Glucocorticoids directly applied to bovine adrenal chromaffin cells decreased STREX exon inclusion in Slo transcripts (effect blocked by glucocorticoid receptor antagonist RU38486), while adrenal androgens (DHEA, androstenedione, testosterone) increased STREX inclusion, demonstrating opposing steroid hormone regulation of Slo alternative splicing.\",\n      \"method\": \"In vitro cell culture of bovine chromaffin cells, RT-PCR quantification of splice variants, pharmacological receptor antagonist experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean pharmacological dissection of receptor-mediated splicing regulation with specific antagonists in primary cells; single lab, two orthogonal approaches (hormone treatment + receptor antagonist)\",\n      \"pmids\": [\"12032350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The slo core-linker domain (transmembrane core through the linker region) is a critical structural determinant of differential BKCa channel responses to ethanol; channels with an mslo-type core-linker are consistently activated by ethanol, while channels with a bslo-type core-linker display heterogeneous responses (inhibition, refractoriness, or activation).\",\n      \"method\": \"Chimeric channel construction (mslo/bslo), single-channel patch-clamp in cell-free membrane patches\",\n      \"journal\": \"Alcoholism, clinical and experimental research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — domain-swap chimera approach with single-channel electrophysiology in cell-free patches; single lab but rigorous mechanistic dissection\",\n      \"pmids\": [\"14574235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In Drosophila, slo gene expression in the nervous system is induced by sedation with benzyl alcohol, and this induction is both necessary and sufficient for rapid drug tolerance: a mutation eliminating slo expression prevents tolerance, while transgenic induction of slo mimics tolerance in naive animals.\",\n      \"method\": \"Genetic loss-of-function mutation, inducible transgene expression, behavioral assay in Drosophila\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with both loss-of-function and gain-of-function (transgene) approaches converging on the same phenotype; rigorous behavioral assay\",\n      \"pmids\": [\"15569939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In Aplysia bag cell neurons, a PKA-regulated splice isoform of slo (slo-a, containing a PKA consensus phosphorylation site) is expressed in adult but not juvenile neurons. PKA reduces open probability of Slo-a channels but has no effect on Slo-b (lacking the site), providing a mechanism for developmental regulation of neuronal excitability and reproductive afterdischarges.\",\n      \"method\": \"cDNA library isolation, CHO cell expression with patch-clamp, immunocytochemistry, PKA pharmacology, native neuron recordings\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro functional assay with defined isoforms plus PKA pharmacology and in vivo confirmation by immunocytochemistry; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"15375169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CaMKII phosphorylates Thr107 on the S0-S1 cytosolic loop of bovine Slo (BK channel); incremental phosphorylation of Thr107 progressively increases channel activity and converts alcohol responses from activation to inhibition, identifying this residue as a molecular switch regulating BK channel function and alcohol responses.\",\n      \"method\": \"Site-directed mutagenesis of Thr107, in vitro CaMKII phosphorylation assay, patch-clamp electrophysiology, ethanol exposure\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis combined with in vitro kinase assay and electrophysiology; single lab but multiple orthogonal methods establishing the phosphorylation-function link\",\n      \"pmids\": [\"16341213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Estrogen progressively downregulates STREX exon inclusion in rat Slo transcripts during pregnancy (near 80% reduction at term), an effect blocked by estrogen receptor antagonist ICI 182,780 and opposed by progesterone, providing a mechanism for pregnancy-related switch in Slo PKA regulation from inhibitory (STREX present) to excitatory (STREX absent).\",\n      \"method\": \"RT-PCR quantification of splice variants during pregnancy, estrogen/progesterone/antagonist treatment of rats\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo pharmacological manipulation plus receptor antagonist with quantitative RT-PCR; single lab, two orthogonal approaches\",\n      \"pmids\": [\"16102753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In C. elegans, slo-1 (encoding a Ca2+-activated K+ channel homologous to mammalian BK/KCNMA1) is required for the anthelmintic action of emodepside; nine alleles of slo-1 recovered in a mutagenesis screen confer high resistance, and tissue-specific rescue shows emodepside acts through SLO-1 in body wall muscle or neurons to inhibit locomotion, and in neurons (not muscle) via a latrophilin-facilitated pathway to inhibit feeding.\",\n      \"method\": \"Forward genetic screen, mutagenesis, tissue-specific genetic rescue, behavioral assays in C. elegans\",\n      \"journal\": \"International journal for parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — forward genetic screen recovering multiple alleles, combined with tissue-specific rescue experiments; independently replicated across several subsequent studies\",\n      \"pmids\": [\"17583712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In mouse distal colon, aldosterone-induced K+ secretion occurs exclusively via luminal KCa1.1 (BK) channels; high-K+ diet causes 2-fold increase in iberiotoxin-sensitive K+ secretion absent in BK alpha-subunit knockout (BK−/−) mice, demonstrating that aldosterone acts through increased BK channel expression to mediate colonic K+ secretion.\",\n      \"method\": \"Ussing chamber electrophysiology, BK knockout mice, pharmacological inhibition (iberiotoxin), immunohistochemistry, mRNA quantification\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (knockout, pharmacology, electrophysiology, IHC) in a well-controlled study; phenotype confirmed in genetic null animals\",\n      \"pmids\": [\"18617563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In mouse submandibular exocrine gland, KCa1.1 channels localize to apical membranes of striated and excretory duct cells and mediate K+ secretion; K+ secretion is reduced >75% in KCa1.1 null mice and by the specific blocker paxilline, whereas KCa3.1 null mice show no change.\",\n      \"method\": \"KCa1.1 knockout mice, paxilline pharmacology, saliva ion measurement, immunohistochemistry, patch-clamp electrophysiology\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null combined with specific pharmacological blocker and direct localization by IHC; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"18216162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KCa1.1 (BK/KCNMA1) is the major potassium channel at the plasma membrane of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS); blocking this channel perturbs calcium homeostasis and inhibits RA-FLS proliferation, VEGF/IL-8/pro-MMP-2 production, and migration/invasion.\",\n      \"method\": \"Patch-clamp electrophysiology, siRNA knockdown, pharmacological channel blockade, proliferation and invasion assays, calcium imaging in primary RA-FLS\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown plus pharmacological blockade with multiple functional readouts in primary human cells; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"22074915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Single-molecule TIRF imaging in living VSMCs shows that BKα subunit mobility on the plasma membrane is restricted by its auxiliary β1 subunit (~50% reduction in diffusion coefficient), by the actin cytoskeleton (cytochalasin D increases mobility), and by direct interaction with caveolin-1 (Cav1; FRET confirmed co-localization), revealing that dynamic regulation of BKα membrane organization involves these three partners.\",\n      \"method\": \"Single-molecule TIRF microscopy, FRET, co-immunoprecipitation, cytoskeletal disruption pharmacology in HEK293 and VSMCs\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — single-molecule live imaging combined with FRET and Co-IP; single lab but multiple orthogonal biophysical methods\",\n      \"pmids\": [\"22301058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MitoBKCa is encoded by the Kcnma1 gene and is targeted to mitochondria by a 50-amino acid C-terminal splice insert; purified cardiomyocyte mitochondria contain a ~140 kDa Kcnma1-derived protein arranged in ~50 nm clusters, and NS1619-mediated cardioprotection is absent in Kcnma1 knockout mice, establishing KCNMA1 as the molecular correlate of mitoBKCa.\",\n      \"method\": \"Biochemical fractionation, Western blotting, electron microscopy of purified mitochondria, Kcnma1 knockout mice, in vivo cardioprotection assay, BK transcript analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (fractionation, EM, genetic knockout ablating cardioprotection, discovery of targeting splice insert); replicated concept by subsequent study\",\n      \"pmids\": [\"23754429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cav3 (T-type) calcium channels physically associate with the transmembrane S0 segment of KCa1.1 (BKα N-terminus) via co-immunoprecipitation from both transfected cells and rat brain; this Cav3-KCa1.1 complex enables Cav3 calcium influx to shift KCa1.1 voltage for activation ~50 mV negative, activating KCa1.1 at low voltages matching the T-type Ca2+ channel profile.\",\n      \"method\": \"Co-immunoprecipitation from brain and transfected tsA-201 cells, patch-clamp electrophysiology with pharmacological blockers and pore-dead Cav3 mutant, native neuron recordings (medial vestibular neurons)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP from brain tissue plus reconstitution in cells with mutagenesis (pore mutant Cav3) and pharmacological dissection; native neuron confirmation\",\n      \"pmids\": [\"23626738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRPV1 channels are functionally coupled with BK (mSlo1/KCNMA1) channels in rat DRG neurons; Ca2+ influx through TRPV1 activates BK channels within submilliseconds (estimated local Ca2+ >10 µM around BK), an effect blocked by 10 mM BAPTA but not 5 mM EGTA, and TRPV1-BK complex formation was confirmed by co-immunoprecipitation and fluorescence co-localization.\",\n      \"method\": \"Patch-clamp electrophysiology (infrared laser TRPV1 activation), co-immunoprecipitation, fluorescence imaging in HEK cells and native DRG neurons\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional coupling demonstrated by fast Ca2+ chelator differential and Co-IP; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24147119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BK channels encoded by KCNMA1 are present in cardiomyocyte mitochondria (mitoplast electrophysiology confirms paxilline- and NS11021-sensitive 190 pS conductance absent in BK−/− mice); BK−/− cardiomyocytes show attenuated oxidative phosphorylation capacity, elevated post-anoxic ROS, and enlarged infarcts upon ischemic pre-conditioning (IP), while infarcts without IP are unchanged, establishing that KCNMA1-encoded mitoBK mediates the beneficial effects of IP partly through modulation of mitochondrial ROS.\",\n      \"method\": \"Mitoplast electrophysiology, BK knockout mice, ex vivo ischemia/reperfusion model, mitochondrial ROS and respiration measurements, electron microscopy\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — electrophysiological confirmation in knockout mitoplasts plus multiple functional readouts (respiration, ROS, infarct area) across genetic null animals; multiple orthogonal methods\",\n      \"pmids\": [\"25072914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Emodepside directly opens C. elegans Slo-1a channels expressed in Xenopus oocytes (1–10 µM emodepside increased currents across a wide range of step potentials in the absence of experimentally increased intracellular Ca2+), and the effect is irreversible upon washout; the Slo-1 inhibitor verruculogen was only effective when applied before, not after, emodepside, indicating a stable drug-channel interaction.\",\n      \"method\": \"Heterologous expression of C. elegans Slo-1a in Xenopus oocytes, voltage-clamp electrophysiology, pharmacological washout and competition experiments\",\n      \"journal\": \"PLoS neglected tropical diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro electrophysiological reconstitution of emodepside action on isolated channel; pharmacological competition establishes binding mechanism; single lab but rigorous voltage-clamp study\",\n      \"pmids\": [\"25521608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"11,12-EET induces smooth muscle hyperpolarization and vascular relaxation in human internal mammary arteries through a TRPV4-TRPC1-KCa1.1 ternary complex; co-immunoprecipitation shows TRPV4, TRPC1, and KCa1.1 physically interact, and TRPC1 is the linker enabling TRPV4-KCa1.1α interaction.\",\n      \"method\": \"Co-immunoprecipitation in human LIMA tissue and HEK293 cells, microelectrode membrane potential recordings, vascular tension assays, siRNA/pharmacological suppression of each component\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP from native tissue plus functional validation in HEK293 cells with domain-specific loss-of-function; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25511389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Human KCNMA1 expressed in C. elegans slo-1 null mutants rescues behavioral deficits of loss of slo-1 signaling, but worms expressing human KCNMA1 are 10–100-fold less sensitive to emodepside than those expressing the nematode channel, demonstrating species-selective pharmacological differences in the emodepside-SLO1 interaction and predicting an emodepside pharmacophore in nematode SLO-1.\",\n      \"method\": \"Transgenic expression of human KCNMA1 in C. elegans slo-1 null mutants, behavioral dose-response assays, pharmacological agonist testing\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — humanized C. elegans rescue genetics with rigorous behavioral pharmacology; replicated in concept by subsequent cross-phyla electrophysiology study\",\n      \"pmids\": [\"21415309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Emodepside differentially modulates human KCNMA1 versus nematode Slo-1 and insect Drosophila Slo in whole-cell voltage clamp: nematode SLO-1 is strongly facilitated (+73%) at 100 nM; human KCNMA1 shows transient facilitation (+33.5%) followed by sustained inhibition (−52.6%) at 100 nM; insect Slo is activated at low Ca2+ but inhibited at higher Ca2+, establishing species-specific pharmacodynamics.\",\n      \"method\": \"Heterologous expression of orthologous SLO channels in voltage-clamp whole-cell recordings, cross-phyla comparison\",\n      \"journal\": \"PLoS neglected tropical diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro electrophysiological comparison of three orthologous channels under identical conditions; single lab but rigorous quantitative voltage-clamp\",\n      \"pmids\": [\"26437177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KCa1.1 channels regulate human skeletal myoblast proliferation, migration, and fusion; blocking KCa1.1 function increases cytosolic Ca2+ and NFκB levels, enhances proliferation, and decreases MMP secretion, migration, and myotube fusion, phenocopying DM1 myoblasts; DM1 myoblasts show loss of plasma membrane expression of KCa1.1 α-subunit, and reintroducing functional KCa1.1 α-subunits into DM1 myoblasts normalizes proliferation and rescues Mef2 expression.\",\n      \"method\": \"Patch-clamp electrophysiology, siRNA knockdown, KCa1.1 α-subunit overexpression rescue, Ca2+ imaging, NFκB assay, proliferation/migration/fusion assays in primary human myoblasts\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function rescue in primary human cells with multiple cellular readouts; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27763639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KCa1.1 (KCNMA1) α-subunit co-immunoprecipitates with β1 integrins in RA-FLS; blocking KCa1.1 disturbs calcium homeostasis, causes sustained Akt phosphorylation and talin recruitment to β1 integrins, and reduces RA-FLS adhesion, migration, and invasion through β1 integrin regulation—but not via α4, α5, or α6 integrins.\",\n      \"method\": \"Co-immunoprecipitation, patch-clamp, Ca2+ imaging, Akt phosphorylation assay, flow cytometry for integrin activation, functional invasion/adhesion assays in human RA-FLS\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating physical association plus mechanistic signaling cascade (Ca2+/Akt/talin/β1-integrin) with multiple functional readouts; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"28428266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Loss-of-function mutation of TMPRSS3 (type II serine protease) in mice impairs outward K+ currents in cochlear inner hair cells (IHCs) and causes absence of KCNMA1 (BK channel) protein at the neck of IHCs, demonstrating that TMPRSS3 is required for proper Kcnma1 channel membrane expression in IHCs.\",\n      \"method\": \"Patch-clamp electrophysiology in Tmprss3 mutant mice, proteomic analysis, immunohistochemistry\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse model with electrophysiology and proteomic/IHC confirmation; single lab, two orthogonal methods, but mechanistic link between TMPRSS3 activity and Kcnma1 trafficking not biochemically resolved\",\n      \"pmids\": [\"23255163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KCNMA1 mutations identified in patients with gain-of-function (GOF) biophysical properties (e.g. D434G, N999S) cause paroxysmal non-kinesigenic dyskinesia and epilepsy (PNKD3), while loss-of-function (LOF) variants are associated with distinct neurological phenotypes including ataxia and developmental delay, establishing a genotype-phenotype correlation for KCNMA1-linked channelopathy.\",\n      \"method\": \"Patch-clamp electrophysiology of patient mutations expressed in HEK cells, exome/genome sequencing of patient cohort\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiological functional characterization of multiple patient alleles; compiled from multiple independent cases but pharmacological mechanisms not fully dissected\",\n      \"pmids\": [\"31427379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Eight novel KCNMA1 loss-of-function variants (e.g. Ser351Tyr, Gly356Arg, Gly375Arg, Ile663Val abolish BK current; Cys413Tyr and Pro805Leu reduce amplitude and shift activation to positive potentials; Asp984Asn reduces amplitude without affecting kinetics) cause a new neurodevelopmental syndrome (Liang-Wang syndrome) characterized by developmental delay, visceral/cardiac malformations, and neurological symptoms.\",\n      \"method\": \"Exome/genome sequencing, patch-clamp electrophysiology of mutant BK channels in heterologous cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct patch-clamp characterization of eight individual patient mutations with defined loss-of-function mechanisms; single study but rigorous electrophysiology on multiple variants\",\n      \"pmids\": [\"31152168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The KCNMA1-N536H de novo mutation produces a gain-of-function BK channel with markedly enhanced voltage-dependent activation; dextroamphetamine treatment completely suppressed dystonia-atonia spells in the affected patient, identifying a functional mechanism and a treatment approach.\",\n      \"method\": \"Patch-clamp electrophysiology of N536H BK channel in heterologous cells, clinical treatment response\",\n      \"journal\": \"Movement disorders\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous patch-clamp characterization of mutation in single study; clinical treatment is a single patient case report\",\n      \"pmids\": [\"32633875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Three KCNMA1 patient variants show distinct BK channel properties: N999S and D434G are gain-of-function (GOF; BKN999S > BKD434G > WT in activity), while H444Q is loss-of-function (LOF). Knockin mice for N999S and D434G show increased BK currents, broadened action potentials, decreased seizure thresholds, and paroxysmal dyskinesia-like immobility after stress; H444Q/WT mice lack these phenotypes, establishing relative pathogenic severity N999S > D434G > H444Q.\",\n      \"method\": \"Heterologous patch-clamp, transgenic knockin mice, in vivo seizure threshold, behavioral dyskinesia assay, dextroamphetamine treatment\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple knockin mouse models with electrophysiology, behavioral, and pharmacological characterization; cross-allele comparison in same genetic background\",\n      \"pmids\": [\"35819138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Two new de novo KCNMA1 loss-of-function variants p.(A172T) and p.(A314T) associated with Liang-Wang syndrome: p.(A172T) abolishes BK current and inhibits Mg2+-dependent gating while shifting G-V curves to positive potentials when co-expressed with WT; p.(A314T) suppresses current amplitude and shifts G-V curves positive with WT. Both variants reduce total and membrane BK protein levels.\",\n      \"method\": \"Patch-clamp electrophysiology in heterologous cells, Western blotting for total and membrane protein\",\n      \"journal\": \"Acta physiologica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — patch-clamp characterization of defined mutations with parallel biochemical quantification of channel protein levels; single lab, two orthogonal methods\",\n      \"pmids\": [\"35156297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The transcription factor Nrf2 directly binds to the antioxidant response element (ARE) of the KCNMA1 promoter (confirmed by luciferase reporter assay) and transcriptionally upregulates BKα (KCNMA1) expression; Nrf2 knockout mice show reduced BKα mRNA and protein in coronary arteries and diminished BK channel current density, whereas adenoviral Nrf2 expression increases BKα protein and BK channel activity in coronary arterial smooth muscle cells.\",\n      \"method\": \"Promoter-luciferase reporter assay, Nrf2 knockout mice, adenoviral overexpression, patch-clamp electrophysiology, Western blotting, qPCR\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct promoter binding assay plus genetic knockout and rescue with multiple orthogonal methods; single lab but comprehensive mechanistic dissection\",\n      \"pmids\": [\"32147517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In human UBSM, PDE inhibition causes ~3.6-fold increase in transient KCa1.1 channel current frequency and membrane hyperpolarization (~5.6 mV); paxilline (KCa1.1 blocker) abolishes spontaneous transient hyperpolarization and the PDE inhibitor-induced hyperpolarization, and eliminates PDE-blocker-induced relaxation of both spontaneous and nerve-evoked contractions, establishing KCa1.1 as the critical effector of cAMP-mediated UBSM relaxation.\",\n      \"method\": \"Patch-clamp electrophysiology, live-cell Ca2+ imaging, isometric tension recording in human UBSM strips, pharmacological blockade with paxilline\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — convergent electrophysiology and contractility data in human tissue with specific pharmacological blockade; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"22896041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In C. elegans, SLO-1 co-localizes with dystrophin homologue DYS-1 in muscle M-lines and dense bodies (Z-lines) by GFP reporter; inactivation of slo-1 in muscles causes progressive degeneration in sensitized backgrounds similar to dys-1 mutations, and single-channel recordings confirm the Ca2+-activated K+ channel in body-wall muscle is SLO-1; channel abundance and conductance are unchanged in dys-1 mutants, suggesting DYS-1 regulates SLO-1 activity rather than expression.\",\n      \"method\": \"GFP reporter localization, genetic epistasis in C. elegans, inside-out patch-clamp electrophysiology of body-wall muscle cells\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct single-channel electrophysiology combined with subcellular localization imaging and genetic epistasis; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"16527307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In C. elegans AWC olfactory neuron differentiation, SLO-1 BK channels act downstream of NSY-5 gap junctions to inhibit voltage-activated calcium channel signaling (UNC-2/CaV2 and EGL-19/CaV1), specifying AWCON identity; nsy-5-dependent asymmetric expression of slo-1 in AWCON is necessary and sufficient for AWC asymmetry; SLO-1 co-localizes with UNC-2 and EGL-19 in AWC, and the auxiliary subunit BKIP-1 is required for SLO-1 and SLO-2 function in this context.\",\n      \"method\": \"Genetic epistasis in C. elegans, tissue-specific rescue, fluorescent localization, GFP reporter analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic epistasis with multiple alleles, tissue-specific rescue, and co-localization; single lab but comprehensive epistatic analysis\",\n      \"pmids\": [\"26771544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"EGF receptor (EGFR) activation in native contractile rat basilar artery smooth muscle cells activates iberiotoxin-sensitive KCa1.1 (maxi-K) channels via an adenylate cyclase type 5 (AC-5)/cAMP-dependent protein kinase (PKA) pathway; EGFR-mediated KCa1.1 activation leads to membrane hyperpolarization and is required for PCNA upregulation, implicating KCa1.1 in EGFR-mediated proliferative signaling.\",\n      \"method\": \"Patch-clamp electrophysiology in freshly isolated VSMCs, antisense knockdown of EGFR and AC-5, PKA inhibitors, in vivo PCNA immunostaining\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology with pharmacological and antisense-mediated dissection of signaling pathway; single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"16284070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Chick β4-subunit increases Slo (BKα) responsiveness to physiological Ca2+ concentrations at hair cell operating voltages (around −50 mV), while both β4 and β1 subunits reduce Slo surface expression; β4 and β1 are preferentially expressed in low-frequency hair cells, providing a molecular basis for electrical tuning in these cells.\",\n      \"method\": \"Cloning of chick β4 and β1 subunits, heterologous expression in oocytes/cells with BKα, electrophysiology, surface expression quantification\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct electrophysiological reconstitution with defined subunit combinations; single lab, multiple functional readouts\",\n      \"pmids\": [\"21178105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In C. elegans, alternative splicing at all three splice sites of slo-1 is coordinated; a point mutation in an intron adjacent to one alternate splice site disrupts coordination at all three sites and causes aberrant neuromuscular junction transmission; a UAAAUC intronic element disrupted by this mutation is enriched in genes with multiple alternate splice sites and appears to act as a cis-regulatory element for intragenic splicing coordination.\",\n      \"method\": \"Quantitative PCR-based splice variant quantification, conditional probability modeling, forward genetics in C. elegans, electrophysiological analysis of NMJ function\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — combination of quantitative splicing analysis, genetic point mutation, and NMJ electrophysiology; single lab\",\n      \"pmids\": [\"22084100\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KCNMA1 encodes the pore-forming α-subunit of the large-conductance, Ca2+- and voltage-activated BK potassium channel, a homotetramer that contains a unique extracellular S0 segment and a large C-terminal cytoplasmic domain harboring multiple ligand-sensing (Ca2+, Mg2+) and regulatory domains; channel gating is positively regulated by membrane depolarization and intracellular Ca2+ (supplied locally by Cav1.2, Cav3, TRPV1, or TRPV4-TRPC1 complexes), is modulated by CaMKII phosphorylation of Thr107 and PKA-dependent phosphorylation of STREX-containing splice isoforms, and is subject to extensive tissue-specific alternative splicing (notably the STREX exon whose inclusion is regulated by glucocorticoids, androgens, estrogen/progesterone, and stress) that inverts PKA regulation and tunes Ca2+/oxidation sensitivity; the channel is transcriptionally regulated by Nrf2 and epigenetically silenced by promoter methylation in some cancers; a specific C-terminal splice insert targets a subpopulation of KCNMA1-encoded channels to cardiac mitochondria (mitoBKCa), where they fine-tune oxidative metabolism and mediate ischemic preconditioning; at the plasma membrane BKα mobility is restricted by its auxiliary β1 subunit, the actin cytoskeleton, and caveolin-1, and functionally it couples to β1-integrins to regulate cell invasiveness; gain-of-function mutations (notably N999S and D434G) cause paroxysmal non-kinesigenic dyskinesia and epilepsy, while loss-of-function mutations cause Liang-Wang syndrome with developmental delay and structural brain abnormalities.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KCNMA1 encodes the pore-forming \\u03b1-subunit of the large-conductance Ca2+- and voltage-activated BK (KCa1.1) potassium channel, originally defined through the Drosophila slo locus whose mutations abolish Ca2+-activated K+ current in muscle and neurons [#0]. Channel output is set by the convergence of membrane depolarization and intracellular Ca2+, which is supplied locally through physical association of BK\\u03b1 with partner Ca2+ sources: the S0 segment binds Cav3 to shift BK voltage-dependence ~50 mV negative [#16], and BK forms co-immunoprecipitating complexes with TRPV1 [#17] and a TRPV4-TRPC1 module [#20] that deliver high local Ca2+ for rapid activation. The large cytoplasmic C-terminus and S0-S1 loop integrate post-translational and splicing inputs: CaMKII phosphorylation of Thr107 graded-tunes activity and inverts ethanol responses [#8], the cysteine-rich STREX splice insert reverses PKA regulation from activation to inhibition and amplifies oxidation and Ca2+ sensitivity [#3], and STREX inclusion is itself controlled by opposing steroid hormones\\u2014glucocorticoids versus androgens [#4] and estrogen versus progesterone [#9]. KCNMA1 channels also assemble as heteromers with related Slack subunits [#2] and are modulated by auxiliary \\u03b21/\\u03b24 subunits that alter Ca2+ sensitivity and surface expression [#36]. At the plasma membrane BK\\u03b1 mobility is restricted by the \\u03b21 subunit, the actin cytoskeleton, and caveolin-1 [#14], and the channel couples to \\u03b21-integrins to control adhesion and invasion [#24]. Functionally, BK mediates K+ secretion in colonic and salivary epithelia [#11, #12], smooth-muscle relaxation downstream of cAMP and EGFR signaling [#32, #35], and proliferation/migration in synoviocytes and myoblasts [#13, #23]; transcription is driven by Nrf2 binding the KCNMA1 promoter ARE [#31]. A distinct C-terminal splice insert targets a population of KCNMA1-encoded channels to cardiac mitochondria, where mitoBKCa modulates oxidative metabolism, ROS, and ischemic preconditioning [#15, #18]. Gain-of-function variants (N999S, D434G) cause paroxysmal non-kinesigenic dyskinesia and epilepsy, while loss-of-function variants cause Liang-Wang syndrome with developmental delay and structural malformations [#26, #27, #29].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established the molecular identity of the Ca2+-activated K+ channel by cloning the Drosophila slo locus, defining the founding gene of the BK family and linking it structurally to voltage-gated K+ channels.\",\n      \"evidence\": \"Genomic/cDNA cloning and loss-of-function genetics in Drosophila\",\n      \"pmids\": [\"1857984\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian KCNMA1 ortholog function not yet addressed\", \"Ca2+-sensing and voltage-sensing domains not yet mapped\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed that alternative splicing of the cytoplasmic region tunes BK voltage-dependence, revealing splicing as a primary mechanism for tissue-specific channel diversity.\",\n      \"evidence\": \"cDNA cloning of a 59-aa insert, Xenopus oocyte expression and electrophysiology\",\n      \"pmids\": [\"9115223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological trigger for inclusion not defined\", \"Effect on Ca2+ sensitivity not addressed here\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated that Slo physically heteromerizes with the related Slack subunit, expanding the channel-output repertoire beyond homotetramers.\",\n      \"evidence\": \"Co-expression in oocytes with single-channel patch-clamp\",\n      \"pmids\": [\"10196543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Native existence and stoichiometry of heteromers not established\", \"Subunit interface not mapped\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the STREX splice insert as a regulatory switch that inverts PKA control and amplifies oxidation/Ca2+ sensitivity, and showed steroid hormones bidirectionally control its inclusion\\u2014linking splicing to endocrine and stress signaling.\",\n      \"evidence\": \"Splice-variant electrophysiology with PKA/oxidation assays; RT-PCR with receptor antagonists in chromaffin cells\",\n      \"pmids\": [\"12016222\", \"12032350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Splicing factors mediating hormone effects not identified\", \"STREX cysteine oxidation chemistry not resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified Thr107 in the S0-S1 loop as a CaMKII-phosphorylated molecular switch grading channel activity and reversing ethanol responses, and showed PKA-regulated splice isoforms tune neuronal excitability developmentally.\",\n      \"evidence\": \"Site-directed mutagenesis, in vitro CaMKII assay, electrophysiology; Aplysia isoform recordings\",\n      \"pmids\": [\"16341213\", \"15375169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo stoichiometry of Thr107 phosphorylation not quantified\", \"Cross-talk between phosphorylation and splice state incompletely defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected BK to cytoskeletal/dystrophin scaffolds in muscle, showing localization to M-lines and Z-lines and a protective role whose disruption mimics dystrophic degeneration.\",\n      \"evidence\": \"GFP localization, genetic epistasis, and single-channel patch-clamp in C. elegans muscle\",\n      \"pmids\": [\"16527307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which DYS-1 regulates channel activity not biochemically defined\", \"Relevance to mammalian muscle not tested here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established BK as the obligatory effector of hormone-driven epithelial K+ secretion, demonstrating physiological transport roles in vivo.\",\n      \"evidence\": \"Ussing chamber electrophysiology, BK knockout mice, iberiotoxin, IHC in colon; later salivary gland knockout study\",\n      \"pmids\": [\"18617563\", \"18216162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream regulation of BK expression by aldosterone not molecularly resolved\", \"Coupling to apical Na+/Cl- transport incompletely defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed BK membrane organization is dynamically constrained by the \\u03b21 subunit, actin, and caveolin-1, and that BK drives proliferation/invasion in pathological fibroblasts and smooth muscle relaxation downstream of cAMP\\u2014extending the channel into structural and proliferative cell biology.\",\n      \"evidence\": \"Single-molecule TIRF/FRET/Co-IP in VSMCs; siRNA and pharmacology in RA-FLS; patch-clamp and tension recording in human UBSM\",\n      \"pmids\": [\"22301058\", \"22074915\", \"22896041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Caveolin-1 binding interface not mapped\", \"Causal sequence linking Ca2+ homeostasis to proliferation incompletely resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified a C-terminal splice insert that targets KCNMA1 channels to cardiac mitochondria (mitoBKCa) and physical complexes with Cav3, TRPV1, and TRPV4-TRPC1 that supply local Ca2+\\u2014establishing both organellar targeting and source-channel coupling.\",\n      \"evidence\": \"Mitochondrial fractionation/EM and knockout cardioprotection; reciprocal Co-IP and reconstitution electrophysiology for Cav3/TRPV1/TRPV4-TRPC1\",\n      \"pmids\": [\"23754429\", \"23626738\", \"24147119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MitoBKCa pore topology and import pathway not resolved\", \"Stoichiometry of source-channel nanodomains not quantified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Functionally confirmed mitoBK by mitoplast electrophysiology and showed it mediates ischemic preconditioning via ROS modulation, defining a metabolic/cardioprotective role distinct from the plasma-membrane channel.\",\n      \"evidence\": \"Mitoplast patch-clamp, BK knockout mice, ex vivo ischemia/reperfusion, ROS/respiration measurements\",\n      \"pmids\": [\"25072914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between mitoBK K+ flux and ROS not fully defined\", \"Channel partners within mitochondria unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated BK regulation of myoblast proliferation/migration/fusion and rescue of disease phenotypes, broadening its role to muscle regeneration and differentiation.\",\n      \"evidence\": \"Patch-clamp, siRNA, \\u03b1-subunit overexpression rescue, and cellular assays in primary human myoblasts\",\n      \"pmids\": [\"27763639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of membrane expression loss in DM1 not resolved\", \"Link between BK and Mef2 transcription not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed BK\\u03b1 physically associates with \\u03b21-integrins and controls a Ca2+/Akt/talin axis governing adhesion and invasion, linking channel activity to integrin signaling specifically.\",\n      \"evidence\": \"Co-IP, patch-clamp, Ca2+ imaging, Akt/talin assays, and invasion assays in RA-FLS\",\n      \"pmids\": [\"28428266\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs scaffolded BK-integrin interaction not distinguished\", \"Generality beyond RA-FLS not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established Nrf2 as a direct transcriptional activator of KCNMA1 via the promoter ARE, linking the channel to oxidative-stress gene programs in vascular smooth muscle.\",\n      \"evidence\": \"Promoter-luciferase, Nrf2 knockout mice, adenoviral overexpression, patch-clamp\",\n      \"pmids\": [\"32147517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other transcriptional regulators not surveyed\", \"Tissue specificity of Nrf2 control not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved the genotype-phenotype architecture of KCNMA1 channelopathy by characterizing gain- and loss-of-function patient variants in cells and knockin mice and linking GOF to dyskinesia/epilepsy and LOF to Liang-Wang syndrome, with a candidate pharmacological intervention.\",\n      \"evidence\": \"Patch-clamp of patient variants, knockin mouse seizure/behavior assays, Western blot of channel levels, dextroamphetamine treatment\",\n      \"pmids\": [\"31427379\", \"31152168\", \"32633875\", \"35819138\", \"35156297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism translating channel GOF to network hyperexcitability incompletely defined\", \"Genotype-treatment matching for LOF patients unestablished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How splice-state, phosphorylation, subunit composition, and partner-channel complexes are integrated in vivo to set BK output in specific tissues, and how this integration is perturbed across the spectrum of disease variants, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model coupling splicing, phosphorylation, and nanodomain assembly\", \"Structural basis of variant pathogenicity incomplete\", \"MitoBK targeting/import mechanism unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 2, 11, 12, 18]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [31]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [16, 17, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [13, 14, 24]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [15, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [\"BK channel (KCNMA1/Slo-Slack heteromer)\", \"Cav3-KCa1.1 complex\", \"TRPV4-TRPC1-KCa1.1 ternary complex\", \"mitoBKCa\"],\n    \"partners\": [\"KCNT1\", \"CACNA1G\", \"TRPV1\", \"TRPV4\", \"TRPC1\", \"CAV1\", \"ITGB1\", \"NFE2L2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}