Target Information

General Information of This Target
Target ID
BTDT00133
Target Name
Calcium-activated potassium channel subunit alpha-1 (KCNMA1)
Target Bioclass
Transporter and channel
Uniprot ID
Q12791
3D Structure
Download
2D Sequence
3D Structure
Source
Predict by Alphafold2
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Alphafold Parameters: msa_mode: mmseqs2_uniref_env model_type: auto num_recycles: auto
Gene Name
KCNMA1
Gene ID
3778
Synonym
KCNMA; SLO; BK channel; BKCA alpha; Calcium-activated potassium channel, subfamily M subunit alpha-1; K(VCA)alpha; KCa1.1; Maxi K channel; Slo-alpha; Slo1; Slowpoke homolog
Sequence
MANGGGGGGGSSGGGGGGGGSSLRMSSNIHANHLSLDASSSSSSSSSSSSSSSSSSSSSS
VHEPKMDALIIPVTMEVPCDSRGQRMWWAFLASSMVTFFGGLFIILLWRTLKYLWTVCCH
CGGKTKEAQKINNGSSQADGTLKPVDEKEEAVAAEVGWMTSVKDWAGVMISAQTLTGRVL
VVLVFALSIGALVIYFIDSSNPIESCQNFYKDFTLQIDMAFNVFFLLYFGLRFIAANDKL
WFWLEVNSVVDFFTVPPVFVSVYLNRSWLGLRFLRALRLIQFSEILQFLNILKTSNSIKL
VNLLSIFISTWLTAAGFIHLVENSGDPWENFQNNQALTYWECVYLLMVTMSTVGYGDVYA
KTTLGRLFMVFFILGGLAMFASYVPEIIELIGNRKKYGGSYSAVSGRKHIVVCGHITLES
VSNFLKDFLHKDRDDVNVEIVFLHNISPNLELEALFKRHFTQVEFYQGSVLNPHDLARVK
IESADACLILANKYCADPDAEDASNIMRVISIKNYHPKIRIITQMLQYHNKAHLLNIPSW
NWKEGDDAICLAELKLGFIAQSCLAQGLSTMLANLFSMRSFIKIEEDTWQKYYLEGVSNE
MYTEYLSSAFVGLSFPTVCELCFVKLKLLMIAIEYKSANRESRILINPGNHLKIQEGTLG
FFIASDAKEVKRAFFYCKACHDDITDPKRIKKCGCKRPKMSIYKRMRRACCFDCGRSERD
CSCMSGRVRGNVDTLERAFPLSSVSVNDCSTSFRAFEDEQPSTLSPKKKQRNGGMRNSPN
TSPKLMRHDPLLIPGNDQIDNMDSNVKKYDSTGMFHWCAPKEIEKVILTRSEAAMTVLSG
HVVVCIFGDVSSALIGLRNLVMPLRASNFHYHELKHIVFVGSIEYLKREWETLHNFPKVS
ILPGTPLSRADLRAVNINLCDMCVILSANQNNIDDTSLQDKECILASLNIKSMQFDDSIG
VLQANSQGFTPPGMDRSSPDNSPVHGMLRQPSITTGVNIPIITELVNDTNVQFLDQDDDD
DPDTELYLTQPFACGTAFAVSVLDSLMSATYFNDNILTLIRTLVTGGATPELEALIAEEN
ALRGGYSTPQTLANRDRCRVAQLALLDGPFADLGDGGCYGDLFCKALKTYNMLCFGIYRL
RDAHLSTPSQCTKRYVITNPPYEFELVPTDLIFCLMQFDHNAGQSRASLSHSSHSSQSSS
KKSSSVHSIPSTANRQNRPKSRESRDKQKYVQEERL

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Family
the potassium channel family
Function
Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+). 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).

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Taxonomy ID
9606
TCDB ID
1.A.1.3.10
        Click to Show/Hide the Complete Species Lineage
Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens
Toxin Information Related to This Target
                           Toxin Name Activity Data Type Activity Data Reference
 Toxin Info    Potassium channel toxin alpha-KTx 1.11 Dissociation constant
1.5 nM
 [1]
 Toxin Info    Potassium channel toxin alpha-KTx 1.1 Dissociation constant
5 nM
 [2]
 Toxin Info    ChTX (K32E) Dissociation constant
26 nM
 [2]
 Toxin Info    IbTx (D19K) Dissociation constant
26 nM
 [3]
 Toxin Info    ChTX (K32D) Dissociation constant
54 nM
 [2]
 Toxin Info    ChTX (K32[Cpa]) Dissociation constant
58 nM
 [2]
 Toxin Info    Potassium channel toxin alpha-KTx 1.3 Inhibition constant
0.94 nM
 [4]
 Toxin Info    IbTx (D19Y,Y36F) Inhibition constant
1.52 nM
 [4]
 Toxin Info    OsK1 (K20D) Inhibition rate . [5]
 Toxin Info    OsK1 (E16K,K20D,T36Y) Inhibition rate . [5]
 Toxin Info    OsK1 (E16K) Inhibition rate . [5]
 Toxin Info    Potassium channel toxin ShK ([pTyr][AEEA]) Inhibition rate . [6]
 Toxin Info    OsK1 (E14A,K18D) Inhibition rate . [7]
 Toxin Info    OsK1 (E15A,K19D) Inhibition rate . [7]
 Toxin Info    OsK1 (E16A,K20D) Inhibition rate . [7]
 Toxin Info    Potassium channel toxin alpha-KTx 23.1 Inhibition rate . [8], [9]
 Toxin Info    Potassium channel toxin alpha-KTx 23.1 Inhibition rate . [9]
 Toxin Info    Neurotoxin HsTX1 (C19[Abu],C34[Abu]) Inhibition rate . [10]
 Toxin Info    U-actitoxin-Oulsp2 Inhibition rate . [11]
 Toxin Info    Kappa-conotoxin RIIIJ Inhibition rate . [12]
 Toxin Info    Kappa-conotoxin RIIIK Inhibition rate . [12]
 Toxin Info    Potassium channel toxin alpha-KTx 4.6 Inhibition rate . [13]
 Toxin Info    U-Asilidin(12)-Dg3b Inhibition rate . [14], [15]
 Toxin Info    Potassium channel toxin alpha-KTx 19.1 Inhibition rate . [16]
 Toxin Info    Potassium channel toxin alpha-KTx 6.3 Inhibition rate . [10]
 Toxin Info    Potassium channel toxin gamma-KTx 2.1 Inhibition rate . [17- 26]
 Toxin Info    Potassium channel toxin gamma-KTx 2.1 Inhibition rate . [17]
 Toxin Info    Mu-scoloptoxin(15)-Ssm1a Inhibition rate . [27]
 Toxin Info    Potassium channel toxin alpha-KTx 16.4 Inhibition rate . [28]
 Toxin Info    Apamin Inhibition rate . [29- 46]
 Toxin Info    Toxin VmKTx1 Inhibition rate . [47]
 Toxin Info    Potassium channel toxin alpha-KTx 3.7 Inhibition rate . [5]
 Toxin Info    Potassium channel toxin alpha-KTx 6.2 Inhibition rate . [48]
 Toxin Info    Potassium channel toxin alpha-KTx 2.13 Inhibition rate . [49]
 Toxin Info    OsK1 (E16K,K20D) Inhibition rate . [5]
 Toxin Info    OsK1 (E16K,K20D) Inhibition rate . [5]
 Toxin Info    Defensin beta 4A Effective concentration 50
1.4 nM
 [50]
 Toxin Info    IbTx (V5Y,Y36F) Effective concentration 50
5.44 nM
 [51]
 Toxin Info    Potassium channel toxin alpha-KTx 1.3 Effective concentration 50
5.81 nM
 [51]
 Toxin Info    R.appendiculatus Kunitz/BPTI-like protein IC50
1 μM
 [52], [53]
References
Ref 1 Slotoxin, alphaKTx1.11, a new scorpion peptide blocker of MaxiK channels that differentiates between alpha and alpha+beta (beta1 or beta4) complexes. FEBS Lett. 2001 Sep 21;505(3):369-73. doi: 10.1016/s0014-5793(01)02791-0.
Ref 2 Structure-guided transformation of charybdotoxin yields an analog that selectively targets Ca(2+)-activated over voltage-gated K(+) channels. J Biol Chem. 2000 Jan 14;275(2):1201-8. doi: 10.1074/jbc.275.2.1201.
Ref 3 Synthesis of a biotin derivative of iberiotoxin: binding interactions with streptavidin and the BK Ca2+-activated K+ channel expressed in a human cell line. Bioconjug Chem. 2006 May-Jun;17(3):689-99. doi: 10.1021/bc060002u.
Ref 4 [125I]Iberiotoxin-D19Y/Y36F, the first selective, high specific activity radioligand for high-conductance calcium-activated potassium channels. Biochemistry. 1997 Feb 18;36(7):1943-52. doi: 10.1021/bi962074m.
Ref 5 K+ channel types targeted by synthetic OSK1, a toxin from Orthochirus scrobiculosus scorpion venom. Biochem J. 2005 Jan 1;385(Pt 1):95-104. doi: 10.1042/BJ20041379.
Ref 6 Targeting effector memory T cells with a selective peptide inhibitor of Kv1.3 channels for therapy of autoimmune diseases. Mol Pharmacol. 2005 Apr;67(4):1369-81. doi: 10.1124/mol.104.008193. Epub 2005 Jan 21.
Ref 7 Pharmacological profiling of Orthochirus scrobiculosus toxin 1 analogs with a trimmed N-terminal domain. Mol Pharmacol. 2006 Jan;69(1):354-62. doi: 10.1124/mol.105.017210. Epub 2005 Oct 18.
Ref 8 Structure, function, and chemical synthesis of Vaejovis mexicanus peptide 24: a novel potent blocker of Kv1.3 potassium channels of human T lymphocytes. Biochemistry. 2012 May 15;51(19):4049-61. doi: 10.1021/bi300060n. Epub 2012 May 7.
Ref 9 Vm24, a natural immunosuppressive peptide, potently and selectively blocks Kv1.3 potassium channels of human T cells. Mol Pharmacol. 2012 Sep;82(3):372-82. doi: 10.1124/mol.112.078006. Epub 2012 May 23.
Ref 10 The impact of the fourth disulfide bridge in scorpion toxins of the alpha-KTx6 subfamily. Proteins. 2005 Dec 1;61(4):1010-23. doi: 10.1002/prot.20681.
Ref 11 Synthesis, folding, structure and activity of a predicted peptide from the sea anemone Oulactis sp. with an ShKT fold. Toxicon. 2018 Aug;150:50-59. doi: 10.1016/j.toxicon.2018.05.006. Epub 2018 May 19.
Ref 12 Biochemical characterization of kappaM-RIIIJ, a Kv1.2 channel blocker: evaluation of cardioprotective effects of kappaM-conotoxins. J Biol Chem. 2010 May 14;285(20):14882-14889. doi: 10.1074/jbc.M109.068486. Epub 2010 Mar 10.
Ref 13 Tst26, a novel peptide blocker of Kv1.2 and Kv1.3 channels from the venom of Tityus stigmurus. Toxicon. 2009 Sep 15;54(4):379-89. doi: 10.1016/j.toxicon.2009.05.023. Epub 2009 Jun 3.
Ref 14 Buzz Kill: Function and Proteomic Composition of Venom from the Giant Assassin Fly Dolopus genitalis (Diptera: Asilidae). Toxins (Basel). 2018 Nov 5;10(11):456. doi: 10.3390/toxins10110456.
Ref 15 Weaponisation 'on the fly': Convergent recruitment of knottin and defensin peptide scaffolds into the venom of predatory assassin flies. Insect Biochem Mol Biol. 2020 Mar;118:103310. doi: 10.1016/j.ibmb.2019.103310. Epub 2019 Dec 21.
Ref 16 BmBKTx1, a novel Ca2+-activated K+ channel blocker purified from the Asian scorpion Buthus martensi Karsch. J Biol Chem. 2004 Aug 13;279(33):34562-9. doi: 10.1074/jbc.M312798200. Epub 2004 Jun 3.
Ref 17 An ERG channel inhibitor from the scorpion Buthus eupeus. J Biol Chem. 2001 Mar 30;276(13):9868-76. doi: 10.1074/jbc.M005973200. Epub 2001 Jan 2.
Ref 18 M-type K+ current inhibition by a toxin fron the scorpion Buthus eupeus. FEBS Lett. 1996 Apr 22;384(3):277-80. doi: 10.1016/0014-5793(96)00333-x.
Ref 19 BeKm-1 is a HERG-specific toxin that shares the structure with ChTx but the mechanism of action with ErgTx1. Biophys J. 2003 May;84(5):3022-36. doi: 10.1016/S0006-3495(03)70028-9.
Ref 20 Preferential closed channel blockade of HERG potassium currents by chemically synthesised BeKm-1 scorpion toxin. FEBS Lett. 2003 Jul 17;547(1-3):20-6. doi: 10.1016/s0014-5793(03)00662-8.
Ref 21 Unique interaction of scorpion toxins with the hERG channel. J Mol Recognit. 2004 May-Jun;17(3):209-17. doi: 10.1002/jmr.667.
Ref 22 Species diversity and peptide toxins blocking selectivity of ether-a-go-go-related gene subfamily K+ channels in the central nervous system. Mol Pharmacol. 2006 May;69(5):1673-83. doi: 10.1124/mol.105.019729. Epub 2006 Feb 23.
Ref 23 BeKm-1, a peptide inhibitor of human ether-a-go-go-related gene potassium currents, prolongs QTc intervals in isolated rabbit heart. J Pharmacol Exp Ther. 2011 Apr;337(1):2-8. doi: 10.1124/jpet.110.176883. Epub 2010 Dec 23.
Ref 24 A large number of novel Ergtoxin-like genes and ERG K+-channels blocking peptides from scorpions of the genus Centruroides. FEBS Lett. 2002 Dec 4;532(1-2):121-6. doi: 10.1016/s0014-5793(02)03652-9.
Ref 25 Interaction simulation of hERG K+ channel with its specific BeKm-1 peptide: insights into the selectivity of molecular recognition. J Proteome Res. 2007 Feb;6(2):611-20. doi: 10.1021/pr060368g.
Ref 26 New binding site on common molecular scaffold provides HERG channel specificity of scorpion toxin BeKm-1. J Biol Chem. 2002 Nov 8;277(45):43104-9. doi: 10.1074/jbc.M204083200. Epub 2002 Jul 31.
Ref 27 Centipedes subdue giant prey by blocking KCNQ channels. Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):1646-1651. doi: 10.1073/pnas.1714760115. Epub 2018 Jan 22.
Ref 28 Molecular divergence of two orthologous scorpion toxins affecting potassium channels. Comp Biochem Physiol A Mol Integr Physiol. 2011 Jul;159(3):313-21. doi: 10.1016/j.cbpa.2011.03.027. Epub 2011 Apr 3.
Ref 29 The precursors of the bee venom constituents apamin and MCD peptide are encoded by two genes in tandem which share the same 3'-exon. J Biol Chem. 1995 May 26;270(21):12704-8. doi: 10.1074/jbc.270.21.12704.
Ref 30 The peptide components of bee venom. Eur J Biochem. 1976 Jan 15;61(2):369-76. doi: 10.1111/j.1432-1033.1976.tb10030.x.
Ref 31 Apamin as a selective blocker of the calcium-dependent potassium channel in neuroblastoma cells: voltage-clamp and biochemical characterization of the toxin receptor. Proc Natl Acad Sci U S A. 1982 Feb;79(4):1308-12. doi: 10.1073/pnas.79.4.1308.
Ref 32 Apamin, a blocker of the calcium-activated potassium channel, induces neurodegeneration of Purkinje cells exclusively. Brain Res. 1997 Dec 19;778(2):405-8. doi: 10.1016/s0006-8993(97)01165-7.
Ref 33 Determinants of apamin and d-tubocurarine block in SK potassium channels. J Biol Chem. 1997 Sep 12;272(37):23195-200. doi: 10.1074/jbc.272.37.23195.
Ref 34 Pharmacological characterization of small-conductance Ca(2+)-activated K(+) channels stably expressed in HEK 293 cells. Br J Pharmacol. 2000 Mar;129(5):991-9. doi: 10.1038/sj.bjp.0703120.
Ref 35 SK3 is an important component of K(+) channels mediating the afterhyperpolarization in cultured rat SCG neurones. J Physiol. 2001 Sep 1;535(Pt 2):323-34. doi: 10.1111/j.1469-7793.2001.00323.x.
Ref 36 Apamin interacts with all subtypes of cloned small-conductance Ca2+-activated K+ channels. Pflugers Arch. 2001 Jan;441(4):544-50. doi: 10.1007/s004240000447.
Ref 37 An amino acid outside the pore region influences apamin sensitivity in small conductance Ca2+-activated K+ channels. J Biol Chem. 2007 Feb 9;282(6):3478-86. doi: 10.1074/jbc.M607213200. Epub 2006 Dec 1.
Ref 38 Apamin reduces neuromuscular transmission by activating inhibitory muscarinic M(2) receptors on motor nerve terminals. Eur J Pharmacol. 2010 Jan 25;626(2-3):239-43. doi: 10.1016/j.ejphar.2009.09.064. Epub 2009 Oct 8.
Ref 39 Allosteric block of KCa2 channels by apamin. J Biol Chem. 2010 Aug 27;285(35):27067-27077. doi: 10.1074/jbc.M110.110072. Epub 2010 Jun 18.
Ref 40 The small neurotoxin apamin blocks not only small conductance Ca(2+) activated K(+) channels (SK type) but also the voltage dependent Kv1.3 channel. Eur Biophys J. 2017 Sep;46(6):517-523. doi: 10.1007/s00249-016-1196-0. Epub 2017 Jan 20.
Ref 41 Apamin inhibits TNF-- and IFN--induced inflammatory cytokines and chemokines via suppressions of NF-B signaling pathway and STAT in human keratinocytes. Pharmacol Rep. 2017 Oct;69(5):1030-1035. doi: 10.1016/j.pharep.2017.04.006. Epub 2017 Apr 18.
Ref 42 Apamin Suppresses LPS-Induced Neuroinflammatory Responses by Regulating SK Channels and TLR4-Mediated Signaling Pathways. Int J Mol Sci. 2020 Jun 17;21(12):4319. doi: 10.3390/ijms21124319.
Ref 43 Apamin from bee venom suppresses inflammation in a murine model of gouty arthritis. J Ethnopharmacol. 2020 Jul 15;257:112860. doi: 10.1016/j.jep.2020.112860. Epub 2020 Apr 11.
Ref 44 Antioxidative, Antiapoptotic, and Anti-Inflammatory Effects of Apamin in a Murine Model of Lipopolysaccharide-Induced Acute Kidney Injury. Molecules. 2020 Dec 3;25(23):5717. doi: 10.3390/molecules25235717.
Ref 45 Solution structure of apamin determined by nuclear magnetic resonance and distance geometry. Biochemistry. 1988 Nov 1;27(22):8491-8. doi: 10.1021/bi00422a029.
Ref 46 Binding and toxicity of apamin. Characterization of the active site. Eur J Biochem. 1991 Mar 28;196(3):639-45. doi: 10.1111/j.1432-1033.1991.tb15860.x.
Ref 47 sVmKTx, a transcriptome analysis-based synthetic peptide analogue of Vm24, inhibits Kv1.3 channels of human T cells with improved selectivity. Biochem Pharmacol. 2022 May;199:115023. doi: 10.1016/j.bcp.2022.115023. Epub 2022 Mar 28.
Ref 48 Maurotoxin: a potent inhibitor of intermediate conductance Ca2+-activated potassium channels. Mol Pharmacol. 2003 Feb;63(2):409-18. doi: 10.1124/mol.63.2.409.
Ref 49 A selective blocker of Kv1.2 and Kv1.3 potassium channels from the venom of the scorpion Centruroides suffusus suffusus. Biochem Pharmacol. 2008 Oct 30;76(9):1142-54. doi: 10.1016/j.bcp.2008.08.018. Epub 2008 Aug 22.
Ref 50 Human -defensin 2 is a novel opener of Ca2+-activated potassium channels and induces vasodilation and hypotension in monkeys. Hypertension. 2013 Aug;62(2):415-25. doi: 10.1161/HYPERTENSIONAHA.111.01076. Epub 2013 Jun 3.
Ref 51 Synthesis and biological evaluation of an iodinated iberiotoxin analogue, [mono-iodo-Tyr5, Phe36]-iberiotoxin. Int J Pept Protein Res. 1996 Aug;48(2):194-9. doi: 10.1111/j.1399-3011.1996.tb00831.x.
Ref 52 An ion-channel modulator from the saliva of the brown ear tick has a highly modified Kunitz/BPTI structure. J Mol Biol. 2009 Jun 19;389(4):734-47. doi: 10.1016/j.jmb.2009.04.045. Epub 2009 Apr 24.
Ref 53 De novo assembly and annotation of the salivary gland transcriptome of Rhipicephalus appendiculatus male and female ticks during blood feeding. Ticks Tick Borne Dis. 2016 Jun;7(4):536-48. doi: 10.1016/j.ttbdis.2016.01.014. Epub 2016 Jan 22.
Ref 54 Pharmaceutical Optimization of Peptide Toxins for Ion Channel Targets: Potent, Selective, and Long-Lived Antagonists of Kv1.3. J Med Chem. 2015 Sep 10;58(17):6784-802. doi: 10.1021/acs.jmedchem.5b00495. Epub 2015 Aug 31.
Ref 55 Design and characterization of a highly selective peptide inhibitor of the small conductance calcium-activated K+ channel, SkCa2. J Biol Chem. 2001 Nov 16;276(46):43145-51. doi: 10.1074/jbc.M106981200. Epub 2001 Aug 29.
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