Affinage

KCNMA1

Calcium-activated potassium channel subunit alpha-1 · UniProt Q12791

Length
1236 aa
Mass
137.6 kDa
Annotated
2026-06-10
100 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1991 High

    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

    PMID:1857984

    Open questions at the time
    • Mammalian KCNMA1 ortholog function not yet addressed
    • Ca2+-sensing and voltage-sensing domains not yet mapped
  2. 1997 High

    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

    PMID:9115223

    Open questions at the time
    • Physiological trigger for inclusion not defined
    • Effect on Ca2+ sensitivity not addressed here
  3. 1998 High

    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

    PMID:10196543

    Open questions at the time
    • Native existence and stoichiometry of heteromers not established
    • Subunit interface not mapped
  4. 2002 High

    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

    PMID:12016222 PMID:12032350

    Open questions at the time
    • Splicing factors mediating hormone effects not identified
    • STREX cysteine oxidation chemistry not resolved
  5. 2005 High

    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

    PMID:15375169 PMID:16341213

    Open questions at the time
    • In vivo stoichiometry of Thr107 phosphorylation not quantified
    • Cross-talk between phosphorylation and splice state incompletely defined
  6. 2006 High

    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

    PMID:16527307

    Open questions at the time
    • Mechanism by which DYS-1 regulates channel activity not biochemically defined
    • Relevance to mammalian muscle not tested here
  7. 2008 High

    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

    PMID:18216162 PMID:18617563

    Open questions at the time
    • Upstream regulation of BK expression by aldosterone not molecularly resolved
    • Coupling to apical Na+/Cl- transport incompletely defined
  8. 2012 High

    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

    PMID:22074915 PMID:22301058 PMID:22896041

    Open questions at the time
    • Caveolin-1 binding interface not mapped
    • Causal sequence linking Ca2+ homeostasis to proliferation incompletely resolved
  9. 2013 High

    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

    PMID:23626738 PMID:23754429 PMID:24147119

    Open questions at the time
    • MitoBKCa pore topology and import pathway not resolved
    • Stoichiometry of source-channel nanodomains not quantified
  10. 2014 High

    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

    PMID:25072914

    Open questions at the time
    • Mechanistic link between mitoBK K+ flux and ROS not fully defined
    • Channel partners within mitochondria unknown
  11. 2016 High

    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

    PMID:27763639

    Open questions at the time
    • Mechanism of membrane expression loss in DM1 not resolved
    • Link between BK and Mef2 transcription not defined
  12. 2017 High

    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

    PMID:28428266

    Open questions at the time
    • Direct vs scaffolded BK-integrin interaction not distinguished
    • Generality beyond RA-FLS not tested
  13. 2020 High

    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

    PMID:32147517

    Open questions at the time
    • Other transcriptional regulators not surveyed
    • Tissue specificity of Nrf2 control not defined
  14. 2022 High

    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

    PMID:31152168 PMID:31427379 PMID:32633875 PMID:35156297 PMID:35819138

    Open questions at the time
    • Mechanism translating channel GOF to network hyperexcitability incompletely defined
    • Genotype-treatment matching for LOF patients unestablished

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No unified model coupling splicing, phosphorylation, and nanodomain assembly
  • Structural basis of variant pathogenicity incomplete
  • MitoBK targeting/import mechanism unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0060089 molecular transducer activity 3 GO:0140110 transcription regulator activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005739 mitochondrion 2
Partners
CACNA1GCAV1ITGB1KCNT1NFE2L2TRPC1TRPV1TRPV4
Complex memberships
BK channel (KCNMA1/Slo-Slack heteromer)Cav3-KCa1.1 complexTRPV4-TRPC1-KCa1.1 ternary complexmitoBKCa

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 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. Genomic and cDNA cloning, sequencing, loss-of-function genetic analysis Science High 1857984
1997 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. cDNA library screening, Xenopus oocyte expression, electrophysiology The Journal of biological chemistry High 9115223
1998 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. Heterologous co-expression in oocytes, single-channel patch-clamp electrophysiology Nature neuroscience High 10196543
2002 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. Splice variant expression in pituitary cells (GH4C1), patch-clamp electrophysiology, PKA/PKG pharmacology, oxidation assays The Journal of biological chemistry High 12016222
2002 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. In vitro cell culture of bovine chromaffin cells, RT-PCR quantification of splice variants, pharmacological receptor antagonist experiments Proceedings of the National Academy of Sciences High 12032350
2003 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). Chimeric channel construction (mslo/bslo), single-channel patch-clamp in cell-free membrane patches Alcoholism, clinical and experimental research High 14574235
2004 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. Genetic loss-of-function mutation, inducible transgene expression, behavioral assay in Drosophila Proceedings of the National Academy of Sciences High 15569939
2004 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. cDNA library isolation, CHO cell expression with patch-clamp, immunocytochemistry, PKA pharmacology, native neuron recordings The Journal of biological chemistry High 15375169
2005 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. Site-directed mutagenesis of Thr107, in vitro CaMKII phosphorylation assay, patch-clamp electrophysiology, ethanol exposure Nature neuroscience High 16341213
2005 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). RT-PCR quantification of splice variants during pregnancy, estrogen/progesterone/antagonist treatment of rats FEBS letters Medium 16102753
2007 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. Forward genetic screen, mutagenesis, tissue-specific genetic rescue, behavioral assays in C. elegans International journal for parasitology High 17583712
2008 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. Ussing chamber electrophysiology, BK knockout mice, pharmacological inhibition (iberiotoxin), immunohistochemistry, mRNA quantification The Journal of physiology High 18617563
2012 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. KCa1.1 knockout mice, paxilline pharmacology, saliva ion measurement, immunohistochemistry, patch-clamp electrophysiology American journal of physiology. Cell physiology High 18216162
2011 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. Patch-clamp electrophysiology, siRNA knockdown, pharmacological channel blockade, proliferation and invasion assays, calcium imaging in primary RA-FLS The Journal of biological chemistry High 22074915
2012 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. Single-molecule TIRF microscopy, FRET, co-immunoprecipitation, cytoskeletal disruption pharmacology in HEK293 and VSMCs American journal of physiology. Cell physiology High 22301058
2013 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. Biochemical fractionation, Western blotting, electron microscopy of purified mitochondria, Kcnma1 knockout mice, in vivo cardioprotection assay, BK transcript analysis Proceedings of the National Academy of Sciences High 23754429
2013 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. 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) PloS one High 23626738
2013 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. Patch-clamp electrophysiology (infrared laser TRPV1 activation), co-immunoprecipitation, fluorescence imaging in HEK cells and native DRG neurons PloS one High 24147119
2014 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. Mitoplast electrophysiology, BK knockout mice, ex vivo ischemia/reperfusion model, mitochondrial ROS and respiration measurements, electron microscopy PloS one High 25072914
2014 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. Heterologous expression of C. elegans Slo-1a in Xenopus oocytes, voltage-clamp electrophysiology, pharmacological washout and competition experiments PLoS neglected tropical diseases High 25521608
2014 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. Co-immunoprecipitation in human LIMA tissue and HEK293 cells, microelectrode membrane potential recordings, vascular tension assays, siRNA/pharmacological suppression of each component Biochimica et biophysica acta High 25511389
2015 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. Transgenic expression of human KCNMA1 in C. elegans slo-1 null mutants, behavioral dose-response assays, pharmacological agonist testing Molecular pharmacology High 21415309
2015 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. Heterologous expression of orthologous SLO channels in voltage-clamp whole-cell recordings, cross-phyla comparison PLoS neglected tropical diseases High 26437177
2016 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. Patch-clamp electrophysiology, siRNA knockdown, KCa1.1 α-subunit overexpression rescue, Ca2+ imaging, NFκB assay, proliferation/migration/fusion assays in primary human myoblasts Cell death & disease High 27763639
2017 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. Co-immunoprecipitation, patch-clamp, Ca2+ imaging, Akt phosphorylation assay, flow cytometry for integrin activation, functional invasion/adhesion assays in human RA-FLS FASEB journal High 28428266
2012 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. Patch-clamp electrophysiology in Tmprss3 mutant mice, proteomic analysis, immunohistochemistry Human molecular genetics Medium 23255163
2019 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. Patch-clamp electrophysiology of patient mutations expressed in HEK cells, exome/genome sequencing of patient cohort The Journal of general physiology Medium 31427379
2019 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. Exome/genome sequencing, patch-clamp electrophysiology of mutant BK channels in heterologous cells Human molecular genetics High 31152168
2020 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. Patch-clamp electrophysiology of N536H BK channel in heterologous cells, clinical treatment response Movement disorders Medium 32633875
2022 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. Heterologous patch-clamp, transgenic knockin mice, in vivo seizure threshold, behavioral dyskinesia assay, dextroamphetamine treatment eLife High 35819138
2022 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. Patch-clamp electrophysiology in heterologous cells, Western blotting for total and membrane protein Acta physiologica High 35156297
2020 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. Promoter-luciferase reporter assay, Nrf2 knockout mice, adenoviral overexpression, patch-clamp electrophysiology, Western blotting, qPCR Journal of molecular and cellular cardiology High 32147517
2012 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. Patch-clamp electrophysiology, live-cell Ca2+ imaging, isometric tension recording in human UBSM strips, pharmacological blockade with paxilline American journal of physiology. Renal physiology High 22896041
2006 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. GFP reporter localization, genetic epistasis in C. elegans, inside-out patch-clamp electrophysiology of body-wall muscle cells Journal of molecular biology High 16527307
2016 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. Genetic epistasis in C. elegans, tissue-specific rescue, fluorescent localization, GFP reporter analysis PLoS genetics High 26771544
2005 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. Patch-clamp electrophysiology in freshly isolated VSMCs, antisense knockdown of EGFR and AC-5, PKA inhibitors, in vivo PCNA immunostaining The Journal of physiology Medium 16284070
2010 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. Cloning of chick β4 and β1 subunits, heterologous expression in oocytes/cells with BKα, electrophysiology, surface expression quantification American journal of physiology. Cell physiology Medium 21178105
2016 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. Quantitative PCR-based splice variant quantification, conditional probability modeling, forward genetics in C. elegans, electrophysiological analysis of NMJ function Proceedings of the National Academy of Sciences Medium 22084100

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1991 A component of calcium-activated potassium channels encoded by the Drosophila slo locus. Science (New York, N.Y.) 550 1857984
2006 High-conductance potassium channels of the SLO family. Nature reviews. Neuroscience 449 17115074
2003 The sodium-activated potassium channel is encoded by a member of the Slo gene family. Neuron 222 12628167
2013 MitoBK(Ca) is encoded by the Kcnma1 gene, and a splicing sequence defines its mitochondrial location. Proceedings of the National Academy of Sciences of the United States of America 174 23754429
1998 Formation of intermediate-conductance calcium-activated potassium channels by interaction of Slack and Slo subunits. Nature neuroscience 145 10196543
1997 A cysteine-rich domain defined by a novel exon in a slo variant in rat adrenal chromaffin cells and PC12 cells. The Journal of biological chemistry 123 9115223
1987 Nucleotide sequence of the streptolysin O (SLO) gene: structural homologies between SLO and other membrane-damaging, thiol-activated toxins. Infection and immunity 119 3502717
2019 KCNMA1-linked channelopathy. The Journal of general physiology 112 31427379
2006 KCNMA1 gene amplification promotes tumor cell proliferation in human prostate cancer. Oncogene 110 17146446
2009 Role of KCNMA1 gene in breast cancer invasion and metastasis to brain. BMC cancer 107 19640305
2000 SLO-2, a K+ channel with an unusual Cl- dependence. Nature neuroscience 102 10903569
2007 The calcium-activated potassium channel, SLO-1, is required for the action of the novel cyclo-octadepsipeptide anthelmintic, emodepside, in Caenorhabditis elegans. International journal for parasitology 93 17583712
2012 Role of KCNMA1 in breast cancer. PloS one 84 22899999
2014 KCNMA1 encoded cardiac BK channels afford protection against ischemia-reperfusion injury. PloS one 80 25072914
2011 Genome wide association study identifies KCNMA1 contributing to human obesity. BMC medical genomics 74 21708048
2019 De novo loss-of-function KCNMA1 variants are associated with a new multiple malformation syndrome and a broad spectrum of developmental and neurological phenotypes. Human molecular genetics 71 31152168
1996 Reconstitution of transcytosis in SLO-permeabilized MDCK cells: existence of an NSF-dependent fusion mechanism with the apical surface of MDCK cells. The EMBO journal 65 8612570
2015 Over-expression of miR-31 or loss of KCNMA1 leads to increased cisplatin resistance in ovarian cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 64 26386726
2008 Aldosterone increases KCa1.1 (BK) channel-mediated colonic K+ secretion. The Journal of physiology 59 18617563
2011 SLO-2 is cytoprotective and contributes to mitochondrial potassium transport. PloS one 58 22145034
2005 CaM kinase II phosphorylation of slo Thr107 regulates activity and ethanol responses of BK channels. Nature neuroscience 57 16341213
2002 Interacting effects of N-terminal variation and strex exon splicing on slo potassium channel regulation by calcium, phosphorylation, and oxidation. The Journal of biological chemistry 56 12016222
2016 Homozygous KCNMA1 mutation as a cause of cerebellar atrophy, developmental delay and seizures. Human genetics 55 27567911
2021 An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy. Channels (Austin, Tex.) 54 34224328
2013 Low voltage activation of KCa1.1 current by Cav3-KCa1.1 complexes. PloS one 52 23626738
2004 slo K(+) channel gene regulation mediates rapid drug tolerance. Proceedings of the National Academy of Sciences of the United States of America 52 15569939
2002 Opposing actions of adrenal androgens and glucocorticoids on alternative splicing of Slo potassium channels in bovine chromaffin cells. Proceedings of the National Academy of Sciences of the United States of America 52 12032350
2016 KCa1.1, a calcium-activated potassium channel subunit alpha 1, is targeted by miR-17-5p and modulates cell migration in malignant pleural mesothelioma. Molecular cancer 46 27245839
2005 Alternative splicing of Slo channel gene programmed by estrogen, progesterone and pregnancy. FEBS letters 46 16102753
2013 Reduction of streptolysin O (SLO) pore-forming activity enhances inflammasome activation. Toxins 45 23744055
2011 SLO-1-channels of parasitic nematodes reconstitute locomotor behaviour and emodepside sensitivity in Caenorhabditis elegans slo-1 loss of function mutants. PLoS pathogens 45 21490955
2014 Characterization of the Ca2+-gated and voltage-dependent K+-channel Slo-1 of nematodes and its interaction with emodepside. PLoS neglected tropical diseases 44 25521608
2011 KCa1.1 potassium channels regulate key proinflammatory and invasive properties of fibroblast-like synoviocytes in rheumatoid arthritis. The Journal of biological chemistry 44 22074915
2008 Apical maxi-K (KCa1.1) channels mediate K+ secretion by the mouse submandibular exocrine gland. American journal of physiology. Cell physiology 44 18216162
2014 Epoxyeicosatrienoic acids act through TRPV4-TRPC1-KCa1.1 complex to induce smooth muscle membrane hyperpolarization and relaxation in human internal mammary arteries. Biochimica et biophysica acta 42 25511389
2008 Genetic variation in the KCNMA1 potassium channel alpha subunit as risk factor for severe essential hypertension and myocardial infarction. Journal of hypertension 40 18854754
2014 SLO-2 potassium channel is an important regulator of neurotransmitter release in Caenorhabditis elegans. Nature communications 38 25300429
2006 The SLO-1 BK channel of Caenorhabditis elegans is critical for muscle function and is involved in dystrophin-dependent muscle dystrophy. Journal of molecular biology 38 16527307
2011 KCa1.1 channel contributes to cell excitability in unmyelinated but not myelinated rat vagal afferents. American journal of physiology. Cell physiology 37 21325638
2017 KCNMA1 cooperating with PTK2 is a novel tumor suppressor in gastric cancer and is associated with disease outcome. Molecular cancer 36 28231797
2017 The Slo(w) path to identifying the mitochondrial channels responsible for ischemic protection. The Biochemical journal 36 28600454
2012 Molecular assembly and dynamics of fluorescent protein-tagged single KCa1.1 channel in expression system and vascular smooth muscle cells. American journal of physiology. Cell physiology 36 22301058
2011 Selective toxicity of the anthelmintic emodepside revealed by heterologous expression of human KCNMA1 in Caenorhabditis elegans. Molecular pharmacology 36 21415309
2011 Intragenic alternative splicing coordination is essential for Caenorhabditis elegans slo-1 gene function. Proceedings of the National Academy of Sciences of the United States of America 35 22084100
2018 Expanding the Phenotype of Homozygous KCNMA1 Mutations; Dyskinesia, Epilepsy, Intellectual Disability, Cerebellar and Corticospinal Tract Atrophy. Balkan medical journal 34 29545233
2002 Simvastatin treatment in the SLO syndrome: a safe approach? American journal of medical genetics 33 12407710
2013 TRPV1 channels are functionally coupled with BK(mSlo1) channels in rat dorsal root ganglion (DRG) neurons. PloS one 32 24147119
2021 Integrating adaptive optics-SLO and OCT for multimodal visualization of the human retinal pigment epithelial mosaic. Biomedical optics express 31 33796365
2013 Transplantation KCNMA1 modified bone marrow-mesenchymal stem cell therapy for diabetes mellitus-induced erectile dysfunction. Andrologia 30 23646921
2006 Regulation of alternative splicing of Slo K+ channels in adrenal and pituitary during the stress-hyporesponsive period of rat development. Endocrinology 30 16675526
2022 BK channel properties correlate with neurobehavioral severity in three KCNMA1-linked channelopathy mouse models. eLife 29 35819138
2020 A Gain-of-Function Mutation in KCNMA1 Causes Dystonia Spells Controlled With Stimulant Therapy. Movement disorders : official journal of the Movement Disorder Society 27 32633875
2019 Group A Streptococcus Induces LAPosomes via SLO/β1 Integrin/NOX2/ROS Pathway in Endothelial Cells That Are Ineffective in Bacterial Killing and Suppress Xenophagy. mBio 27 31575768
2015 The Cyclooctadepsipeptide Anthelmintic Emodepside Differentially Modulates Nematode, Insect and Human Calcium-Activated Potassium (SLO) Channel Alpha Subunits. PLoS neglected tropical diseases 27 26437177
2015 KCa1.1 inhibition attenuates fibroblast-like synoviocyte invasiveness and ameliorates disease in rat models of rheumatoid arthritis. Arthritis & rheumatology (Hoboken, N.J.) 26 25252152
2019 Comparative gain-of-function effects of the KCNMA1-N999S mutation on human BK channel properties. Journal of neurophysiology 25 31851553
2017 Behavioral Deficits Following Withdrawal from Chronic Ethanol Are Influenced by SLO Channel Function in Caenorhabditis elegans. Genetics 25 28546434
2012 Aldosterone induces active K⁺ secretion by enhancing mucosal expression of Kcnn4c and Kcnma1 channels in rat distal colon. American journal of physiology. Cell physiology 25 22322970
2012 Tmprss3 loss of function impairs cochlear inner hair cell Kcnma1 channel membrane expression. Human molecular genetics 25 23255163
2018 Targeting KCa1.1 Channels with a Scorpion Venom Peptide for the Therapy of Rat Models of Rheumatoid Arthritis. The Journal of pharmacology and experimental therapeutics 24 29453198
2012 Worms take to the slo lane: a perspective on the mode of action of emodepside. Invertebrate neuroscience : IN 24 22539031
2007 SLO, SLO, quick, quick, slow: calcium-activated potassium channels as regulators of Caenorhabditis elegans behaviour and targets for anthelmintics. Invertebrate neuroscience : IN 23 17962986
2019 KCNMA1 Expression is Downregulated in Colorectal Cancer via Epigenetic Mechanisms. Cancers 22 30791468
2008 Deficit of Kcnma1 mRNA expression in the dentate gyrus of epileptic rats. Neuroreport 22 18695509
2004 Regulation of Slo potassium channel alternative splicing in the pituitary by gonadal testosterone. Journal of neuroendocrinology 22 15049854
2010 β4-subunit increases Slo responsiveness to physiological Ca2+ concentrations and together with β1 reduces surface expression of Slo in hair cells. American journal of physiology. Cell physiology 21 21178105
2006 Diabetes-induced changes in the alternative splicing of the slo gene in corporal tissue. European urology 21 17150299
2017 KCa1.1 channels regulate β1-integrin function and cell adhesion in rheumatoid arthritis fibroblast-like synoviocytes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20 28428266
2017 Mus musculus-microRNA-449a ameliorates neuropathic pain by decreasing the level of KCNMA1 and TRPA1, and increasing the level of TPTE. Molecular medicine reports 20 28498403
2016 SLO BK Potassium Channels Couple Gap Junctions to Inhibition of Calcium Signaling in Olfactory Neuron Diversification. PLoS genetics 20 26771544
2005 Adenylate cyclase 5 and KCa1.1 channel are required for EGFR up-regulation of PCNA in native contractile rat basilar artery smooth muscle. The Journal of physiology 20 16284070
2003 Distinct regions of the slo subunit determine differential BKCa channel responses to ethanol. Alcoholism, clinical and experimental research 20 14574235
2020 Gene-gene and gene-lifestyle interactions of AKAP11, KCNMA1, PUM1, SPTBN1, and EPDR1 on osteoporosis risk in middle-aged adults. Nutrition (Burbank, Los Angeles County, Calif.) 19 32619791
2016 Different expression of β subunits of the KCa1.1 channel by invasive and non-invasive human fibroblast-like synoviocytes. Arthritis research & therapy 19 27165430
2016 Functional KCa1.1 channels are crucial for regulating the proliferation, migration and differentiation of human primary skeletal myoblasts. Cell death & disease 19 27763639
2015 Effect of scanning beam size on the lateral resolution of mouse retinal imaging with SLO. Optics letters 19 26670523
2002 Autonomous expression of the slo gene of the bicistronic nga-slo operon of Streptococcus pyogenes. Infection and immunity 19 11953421
2020 Human Serum Albumin Binds Streptolysin O (SLO) Toxin Produced by Group A Streptococcus and Inhibits Its Cytotoxic and Hemolytic Effects. Frontiers in immunology 18 33363530
2019 KCa1.1 and Kv1.3 channels regulate the interactions between fibroblast-like synoviocytes and T lymphocytes during rheumatoid arthritis. Arthritis research & therapy 18 30612588
1998 Exoenzyme S from P. aeruginosa ADP ribosylates rab4 and inhibits transferrin recycling in SLO-permeabilized reticulocytes. Biochemical and biophysical research communications 18 9514923
2018 Downregulation of the long noncoding RNA MBNL1-AS1 protects sevoflurane-pretreated mice against ischemia-reperfusion injury by targeting KCNMA1. Experimental & molecular medicine 17 30185781
2015 Enhancement of tumor initiation and expression of KCNMA1, MORF4L2 and ASPM genes in the adenocarcinoma of lung xenograft after vorinostat treatment. Oncotarget 17 25796627
2012 Role of the BK channel (KCa1.1) during activation of electrogenic K+ secretion in guinea pig distal colon. American journal of physiology. Gastrointestinal and liver physiology 17 23064759
2022 Molecular Mechanisms of Epileptic Encephalopathy Caused by KCNMA1 Loss-of-Function Mutations. Frontiers in pharmacology 16 35095492
2022 Identification and functional analysis of two new de novo KCNMA1 variants associated with Liang-Wang syndrome. Acta physiologica (Oxford, England) 16 35156297
2018 Visual Fixation Instability in Multiple Sclerosis Measured Using SLO-OCT. Investigative ophthalmology & visual science 16 29340646
2015 KCa1.1 is potential marker for distinguishing Ah-type baroreceptor neurons in NTS and contributes to sex-specific presynaptic neurotransmission in baroreflex afferent pathway. Neuroscience letters 16 26219983
2009 Inhibition of vascular calcium-gated chloride currents by blockers of KCa1.1, but not by modulators of KCa2.1 or KCa2.3 channels. British journal of pharmacology 16 19645713
2003 Subordination stress alters alternative splicing of the Slo gene in tree shrew adrenals. Hormones and behavior 16 12614648
2002 Pictogram naming in dyslexic and normal children assessed by SLO. Vision research 16 11888544
2020 Regulation of KCNMA1 transcription by Nrf2 in coronary arterial smooth muscle cells. Journal of molecular and cellular cardiology 15 32147517
2017 Survival and growth of C57BL/6J mice lacking the BK channel, Kcnma1: lower adult body weight occurs together with higher body fat. Physiological reports 15 28242822
2013 Enhanced K(+) secretion in dextran sulfate-induced colitis reflects upregulation of large conductance apical K(+) channels (BK; Kcnma1). American journal of physiology. Cell physiology 15 23986198
2011 The secretory KCa1.1 channel localises to crypts of distal mouse colon: functional and molecular evidence. Pflugers Archiv : European journal of physiology 15 21822598
2021 Lisdexamfetamine Therapy in Paroxysmal Non-kinesigenic Dyskinesia Associated with the KCNMA1-N999S Variant. Movement disorders clinical practice 14 35141357
2016 A DNA element in the slo gene modulates ethanol tolerance. Alcohol (Fayetteville, N.Y.) 14 26992698
2016 BK Knockout by TALEN-Mediated Gene Targeting in Osteoblasts: KCNMA1 Determines the Proliferation and Differentiation of Osteoblasts. Molecules and cells 14 27329042
2015 Active Site Dynamical Effects in the Hydrogen Transfer Rate-limiting Step in the Catalysis of Linoleic Acid by Soybean Lipoxygenase-1 (SLO-1): Primary and Secondary Isotope Contributions. The journal of physical chemistry. B 14 26079999
2004 The appearance of a protein kinase A-regulated splice isoform of slo is associated with the maturation of neurons that control reproductive behavior. The Journal of biological chemistry 14 15375169
2012 Constitutively active phosphodiesterase activity regulates urinary bladder smooth muscle function: critical role of KCa1.1 channel. American journal of physiology. Renal physiology 13 22896041

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