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Gene Review

KCNMA1  -  potassium channel, calcium activated large...

Homo sapiens

Synonyms: BK channel, BKCA alpha, BKTM, Calcium-activated potassium channel subunit alpha-1, Calcium-activated potassium channel, subfamily M subunit alpha-1, ...
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Disease relevance of KCNMA1

  • METHODS: Interaction of FAK with the C terminus of the hSlo alpha-subunit of BK was investigated using the yeast two-hybrid system as well as immunofluorescence microscopy and coimmunoprecipitation experiments with a rabbit anti-hslo antibody on MG63 and CAL72 human osteosarcoma cell lines and on normal human osteoblasts [1].
  • Here we report a genetic locus associated with a human syndrome of coexistent generalized epilepsy and paroxysmal dyskinesia on chromosome 10q22 and show that a mutation of the alpha subunit of the BK channel causes this syndrome [2].
  • Under these experimental conditions, hypoxia caused significant channel inhibition only in the presence of 300 nM Ca2+i. Thus, since regulation was observed in excised patches, maxi-K channel inhibition by hypoxia does not require soluble intracellular components and, mechanistically, is voltage independent and Ca2+i sensitive [3].
  • Here we report the isolation, cloning, and functional characterization of glioma BK (gBK), a novel splice isoform of hSlo, the gene that encodes the alpha-subunits of human BK channels [4].
  • Our study provides the first genetic evidence for the different impact of the BK channel in the control of human blood pressure in men and women, with particular relevance in aging women, and highlights the E65K polymorphism as one of the strongest genetic factors associated thus far to protection against myocardial infarction and stroke [5].
  • KCNMA1 qualifies as a promising diagnostic and therapeutic target in patients with prostate cancer [6].

Psychiatry related information on KCNMA1

  • Smith-Lemli-Opitz (SLO or RSH) syndrome is characterized by multiple congenital anomalies, mental retardation, and defective growth; it results from an inherited defect in the biosynthesis of cholesterol [7].
  • OBJECTIVE: To test the safety of a single intracavernous injection of a plasmid vector (hMaxi-K) that expresses the hSlo gene, that encodes the alpha-subunit of the Maxi-K channel, for the treatment of erectile dysfunction (ED) [8].

High impact information on KCNMA1


Chemical compound and disease context of KCNMA1


Biological context of KCNMA1


Anatomical context of KCNMA1

  • Interestingly, these two clusters, near CTNNA3 and KCNMA1 and each containing five genes with down-regulated expression in androgenetic placentas, coincided with the regions with maximal maternal allele sharing seen in the pre-eclamptic sisters [18].
  • Focal adhesion kinase pp125FAK interacts with the large conductance calcium-activated hSlo potassium channel in human osteoblasts: potential role in mechanotransduction [1].
  • Multiple cell-signaling pathways converge to modulate large-conductance, voltage- and Ca2+-sensitive K+ channel (maxi-K channel) activity and buffer cell excitability in human myometrial smooth muscle cells (hMSMCs) [19].
  • Maxi-K channels localize to caveolae in human myometrium: a role for an actin-channel-caveolin complex in the regulation of myometrial smooth muscle K+ current [19].
  • These data indicate that the actin cytoskeleton is involved as part of a caveolar complex in the regulation of myometrial maxi-K channel function [19].

Associations of KCNMA1 with chemical compounds

  • The BK channel in vascular smooth muscle is formed by an ion-conducting alpha subunit and a regulatory beta(1) subunit, which couples local increases in intracellular Ca(2+) to augmented channel activity and vascular relaxation [20].
  • In agreement, coronary muscle MaxiK currents were enhanced by Lavendustin A [17].
  • Cholesterol depletion redistributed the BK channels to non-caveolar fractions of BAECs, resulting in BK channel activation (7.3 +/- 1.6 pA/picofarad (pF), n = 5) [21].
  • Inclusion of a caveolin-1 scaffolding domain peptide (10 microM) in the pipette solution completely abrogated the effects of ISO on BK channel activation, whereas inclusion of the scrambled control peptide (10 microM) did not inhibit the ISO effects [21].
  • This PGE2-mediated channel opening induces the recruitment of various tyrosine-phosphorylated proteins on the hSlo alpha-subunit of BK [12].

Physical interactions of KCNMA1


Regulatory relationships of KCNMA1

  • Herein, we report a transmembrane beta subunit (beta2) that yields inactivating MaxiK currents on coexpression with the pore-forming alpha subunit of MaxiK channels [27].
  • Taken together, these data show that the pore-forming alpha subunit of the hSlo channel promotes N-linked glycosylation of its auxiliary beta4 subunit, and this in turn influences the modulation of the channel by the beta4 subunit [22].
  • As shown by RT-PCR, blockade of MaxiK by paxilline also inhibits induction of the mRNA of TNF-alpha and IL-6 [28].
  • Cytokine production initiated by several Toll-like receptor (TLR) ligands and by interleukin-1 is inhibited by MaxiK blockade [29].
  • Thus, these results permit us to identify the maxi-K channel as the molecular target of E2 that regulates cell proliferation independently of the estrogen receptor [30].

Other interactions of KCNMA1

  • RT-PCR analysis showed expression of P2Y(1), P2Y(2), P2Y(11), P2X(1), P2X(4), and P2X(7) receptors, large-conductance (KCNMA1 and KCNMB1-4), and intermediate-conductance (KCNN4) Ca(2+)-activated K(+) channels [31].
  • We show that FAK/hSlo interaction likely takes place through the Pro-1-rich domain situated in the C-terminal region of the kinase [1].
  • We coexpressed BK channel alpha (BKalpha) and BKbeta4 subunits in vitro in CHO cells [32].
  • To explore the functional role of SV1, we coexpressed SV1 with the alpha (human SLO) and beta1 (KCNMB1) subunits of the MaxiK channel [33].
  • Statistical analysis with the KCNMA1, HTR7 and SLC18A2 genes, which lie in the support region of interest revealed no evidence for association after correction for multiple comparisons [34].

Analytical, diagnostic and therapeutic context of KCNMA1


  1. Focal adhesion kinase pp125FAK interacts with the large conductance calcium-activated hSlo potassium channel in human osteoblasts: potential role in mechanotransduction. Rezzonico, R., Cayatte, C., Bourget-Ponzio, I., Romey, G., Belhacene, N., Loubat, A., Rocchi, S., Van Obberghen, E., Girault, J.A., Rossi, B., Schmid-Antomarchi, H. J. Bone Miner. Res. (2003) [Pubmed]
  2. Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder. Du, W., Bautista, J.F., Yang, H., Diez-Sampedro, A., You, S.A., Wang, L., Kotagal, P., Lüders, H.O., Shi, J., Cui, J., Richerson, G.B., Wang, Q.K. Nat. Genet. (2005) [Pubmed]
  3. Hypoxia inhibits human recombinant large conductance, Ca(2+)-activated K(+) (maxi-K) channels by a mechanism which is membrane delimited and Ca(2+) sensitive. Lewis, A., Peers, C., Ashford, M.L., Kemp, P.J. J. Physiol. (Lond.) (2002) [Pubmed]
  4. Cloning and characterization of glioma BK, a novel BK channel isoform highly expressed in human glioma cells. Liu, X., Chang, Y., Reinhart, P.H., Sontheimer, H., Chang, Y. J. Neurosci. (2002) [Pubmed]
  5. Protective effect of the KCNMB1 E65K genetic polymorphism against diastolic hypertension in aging women and its relevance to cardiovascular risk. Sentí, M., Fernández-Fernández, J.M., Tomás, M., Vázquez, E., Elosua, R., Marrugat, J., Valverde, M.A. Circ. Res. (2005) [Pubmed]
  6. KCNMA1 gene amplification promotes tumor cell proliferation in human prostate cancer. Bloch, M., Ousingsawat, J., Simon, R., Schraml, P., Gasser, T.C., Mihatsch, M.J., Kunzelmann, K., Bubendorf, L. Oncogene (2007) [Pubmed]
  7. Biochemical variants of Smith-Lemli-Opitz syndrome. Neklason, D.W., Andrews, K.M., Kelley, R.I., Metherall, J.E. Am. J. Med. Genet. (1999) [Pubmed]
  8. The first human trial for gene transfer therapy for the treatment of erectile dysfunction: preliminary results. Melman, A., Bar-Chama, N., McCullough, A., Davies, K., Christ, G. Eur. Urol. (2005) [Pubmed]
  9. Selective activation of Ca2+-activated K+ channels by co-localized Ca2+ channels in hippocampal neurons. Marrion, N.V., Tavalin, S.J. Nature (1998) [Pubmed]
  10. Potassium channel stimulation by natriuretic peptides through cGMP-dependent dephosphorylation. White, R.E., Lee, A.B., Shcherbatko, A.D., Lincoln, T.M., Schonbrunn, A., Armstrong, D.L. Nature (1993) [Pubmed]
  11. Acute activation of Maxi-K channels (hSlo) by estradiol binding to the beta subunit. Valverde, M.A., Rojas, P., Amigo, J., Cosmelli, D., Orio, P., Bahamonde, M.I., Mann, G.E., Vergara, C., Latorre, R. Science (1999) [Pubmed]
  12. Prostaglandin E2 induces interaction between hSlo potassium channel and Syk tyrosine kinase in osteosarcoma cells. Rezzonico, R., Schmid-Alliana, A., Romey, G., Bourget-Ponzio, I., Breuil, V., Breittmayer, V., Tartare-Deckert, S., Rossi, B., Schmid-Antomarchi, H. J. Bone Miner. Res. (2002) [Pubmed]
  13. Effects of nitric oxide on expressions of nitrosocysteine and calcium-activated potassium channels in the supraoptic nuclei and neural lobe of dehydrated rats. Kadekaro, M., Su, G., Chu, R., Lei, Y., Li, J., Fang, L. Neurosci. Lett. (2007) [Pubmed]
  14. BK channel openers inhibit migration of human glioma cells. Kraft, R., Krause, P., Jung, S., Basrai, D., Liebmann, L., Bolz, J., Patt, S. Pflugers Arch. (2003) [Pubmed]
  15. Interacting effects of N-terminal variation and strex exon splicing on slo potassium channel regulation by calcium, phosphorylation, and oxidation. Erxleben, C., Everhart, A.L., Romeo, C., Florance, H., Bauer, M.B., Alcorta, D.A., Rossie, S., Shipston, M.J., Armstrong, D.L. J. Biol. Chem. (2002) [Pubmed]
  16. Diversity of Ca(2+)-activated K(+) channel transcripts in inner ear hair cells. Beisel, K.W., Rocha-Sanchez, S.M., Ziegenbein, S.J., Morris, K.A., Kai, C., Kawai, J., Carninci, P., Hayashizaki, Y., Davis, R.L. Gene (2007) [Pubmed]
  17. Coupling of c-Src to large conductance voltage- and Ca2+-activated K+ channels as a new mechanism of agonist-induced vasoconstriction. Alioua, A., Mahajan, A., Nishimaru, K., Zarei, M.M., Stefani, E., Toro, L. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  18. The parent-of-origin effect of 10q22 in pre-eclamptic females coincides with two regions clustered for genes with down-regulated expression in androgenetic placentas. Oudejans, C.B., Mulders, J., Lachmeijer, A.M., van Dijk, M., Könst, A.A., Westerman, B.A., van Wijk, I.J., Leegwater, P.A., Kato, H.D., Matsuda, T., Wake, N., Dekker, G.A., Pals, G., ten Kate, L.P., Blankenstein, M.A. Mol. Hum. Reprod. (2004) [Pubmed]
  19. Maxi-K channels localize to caveolae in human myometrium: a role for an actin-channel-caveolin complex in the regulation of myometrial smooth muscle K+ current. Brainard, A.M., Miller, A.J., Martens, J.R., England, S.K. Am. J. Physiol., Cell Physiol. (2005) [Pubmed]
  20. Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension. Fernández-Fernández, J.M., Tomás, M., Vázquez, E., Orio, P., Latorre, R., Sentí, M., Marrugat, J., Valverde, M.A. J. Clin. Invest. (2004) [Pubmed]
  21. Caveolae targeting and regulation of large conductance Ca(2+)-activated K+ channels in vascular endothelial cells. Wang, X.L., Ye, D., Peterson, T.E., Cao, S., Shah, V.H., Katusic, Z.S., Sieck, G.C., Lee, H.C. J. Biol. Chem. (2005) [Pubmed]
  22. Reciprocal modulation between the alpha and beta 4 subunits of hSlo calcium-dependent potassium channels. Jin, P., Weiger, T.M., Levitan, I.B. J. Biol. Chem. (2002) [Pubmed]
  23. Cilostazol enhances casein kinase 2 phosphorylation and suppresses tumor necrosis factor-alpha-induced increased phosphatase and tensin homolog deleted from chromosome 10 phosphorylation and apoptotic cell death in SK-N-SH cells. Kim, K.Y., Shin, H.K., Lee, J.H., Kim, C.D., Lee, W.S., Rhim, B.Y., Shin, Y.W., Hong, K.W. J. Pharmacol. Exp. Ther. (2004) [Pubmed]
  24. Anti-apoptotic action of (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine (KR-31378) by suppression of the phosphatase and tensin homolog deleted from chromosome 10 phosphorylation and increased phosphorylation of casein kinase2/Akt/ cyclic AMP response element binding protein via maxi-K channel opening in neuronal cells. Kim, K.Y., Lee, J.H., Park, J.H., Yoo, M.A., Kwak, Y.G., Kim, S.O., Yoo, S.E., Hong, K.W. Eur. J. Pharmacol. (2004) [Pubmed]
  25. Cilostazol prevents remnant lipoprotein particle-induced monocyte adhesion to endothelial cells by suppression of adhesion molecules and monocyte chemoattractant protein-1 expression via lectin-like receptor for oxidized low-density lipoprotein receptor activation. Park, S.Y., Lee, J.H., Kim, Y.K., Kim, C.D., Rhim, B.Y., Lee, W.S., Hong, K.W. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  26. Interaction of agitoxin2, charybdotoxin, and iberiotoxin with potassium channels: selectivity between voltage-gated and Maxi-K channels. Gao, Y.D., Garcia, M.L. Proteins (2003) [Pubmed]
  27. Molecular basis of fast inactivation in voltage and Ca2+-activated K+ channels: a transmembrane beta-subunit homolog. Wallner, M., Meera, P., Toro, L. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  28. The role of membrane-bound LBP, endotoxin aggregates, and the MaxiK channel in LPS-induced cell activation. Müller, M., Scheel, O., Lindner, B., Gutsmann, T., Seydel, U. J. Endotoxin Res. (2003) [Pubmed]
  29. Cell activation by ligands of the toll-like receptor and interleukin-1 receptor family depends on the function of the large-conductance potassium channel MaxiK in human macrophages. Scheel, O., Papavlassopoulos, M., Blunck, R., Gebert, A., Hartung, T., Zähringer, U., Seydel, U., Schromm, A.B. Infect. Immun. (2006) [Pubmed]
  30. 17-beta-estradiol activates maxi-K channels through a non-genomic pathway in human breast cancer cells. Coiret, G., Matifat, F., Hague, F., Ouadid-Ahidouch, H. FEBS Lett. (2005) [Pubmed]
  31. Extracellular ATP induces oscillations of intracellular Ca2+ and membrane potential and promotes transcription of IL-6 in macrophages. Hanley, P.J., Musset, B., Renigunta, V., Limberg, S.H., Dalpke, A.H., Sus, R., Heeg, K.M., Preisig-Müller, R., Daut, J. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  32. hKCNMB3 and hKCNMB4, cloning and characterization of two members of the large-conductance calcium-activated potassium channel beta subunit family. Behrens, R., Nolting, A., Reimann, F., Schwarz, M., Waldschütz, R., Pongs, O. FEBS Lett. (2000) [Pubmed]
  33. A novel MaxiK splice variant exhibits dominant-negative properties for surface expression. Zarei, M.M., Zhu, N., Alioua, A., Eghbali, M., Stefani, E., Toro, L. J. Biol. Chem. (2001) [Pubmed]
  34. Autosomal linkage analysis for the level of response to alcohol. Schuckit, M.A., Wilhelmsen, K., Smith, T.L., Feiler, H.S., Lind, P., Lange, L.A., Kalmijn, J. Alcohol. Clin. Exp. Res. (2005) [Pubmed]
  35. Daily rhythmicity of large-conductance Ca2+ -activated K+ currents in suprachiasmatic nucleus neurons. Pitts, G.R., Ohta, H., McMahon, D.G. Brain Res. (2006) [Pubmed]
  36. Identification of a novel tetramerization domain in large conductance K(ca) channels. Quirk, J.C., Reinhart, P.H. Neuron (2001) [Pubmed]
  37. Determinant for beta-subunit regulation in high-conductance voltage-activated and Ca(2+)-sensitive K+ channels: an additional transmembrane region at the N terminus. Wallner, M., Meera, P., Toro, L. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
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