KCNMA1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesKCNMA1, BKTM, KCa1.1, MaxiK, SAKCA, SLO, SLO-ALPHA, SLO1, bA205K10.1, mSLO1, hSlo, potassium calcium-activated channel subfamily M alpha 1, CADEDS, PNKD3, IEG16, LIWAS
External IDsOMIM: 600150 MGI: 99923 HomoloGene: 1693 GeneCards: KCNMA1
Orthologs
SpeciesHumanMouse
Entrez

3778

16531

Ensembl

ENSG00000156113

ENSMUSG00000063142

UniProt

Q12791

Q08460

RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)Chr 10: 76.87 – 77.64 MbChr 14: 23.34 – 24.06 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Calcium-activated potassium channel subunit alpha-1 also known as large conductance calcium-activated potassium channel, subfamily M, alpha member 1 (KCa1.1), or BK channel alpha subunit,[5] is a voltage gated potassium channel encoded by the KCNMA1 gene and characterized by their large conductance of potassium ions (K+) through cell membranes.[6]

Function

BK channels are activated (opened) by changes in membrane electrical potential and/or by increases in concentration of intracellular calcium ion (Ca2+).[7][8] Opening of BK channels allows K+ to passively flow through the channel, down the electrochemical gradient. Under typical physiological conditions, this results in an efflux of K+ from the cell, which leads to cell membrane hyperpolarization (a decrease in the electrical potential across the cell membrane) and a decrease in cell excitability (a decrease in the probability that the cell will transmit an action potential).

BK channels are essential for the regulation of several key physiological processes including smooth muscle tone and neuronal excitability.[6] They control the contraction of smooth muscle and are involved with the electrical tuning of hair cells in the cochlea. BK channels also contribute to the behavioral effects of ethanol in the worm C. elegans under high concentrations (> 100 mM, or approximately 0.50% BAC).[9] It remains to be determined if BK channels contribute to intoxication in humans.

Structure

BK channels have a tetrameric structure. Each monomer of the channel-forming alpha subunit is the product of the KCNMA1 gene. Modulatory beta subunits (encoded by KCNMB1, KCNMB2, KCNMB3, or KCNMB4) can associate with the tetrameric channel. Alternatively spliced transcript variants encoding different isoforms have been identified.[6]

Each BK channel alpha subunit consists of (from N- to C-terminal):

  1. A unique transmembrane domain (S0)[10] that precedes the 6 transmembrane domains (S1-S6) conserved in all voltage-dependent K+ channels.
  2. A voltage sensing domain (S1-S4).
  3. A K+ channel pore domain (S5, selectivity filter, and S6).
  4. A cytoplasmic C-terminal domain (CTD) consisting of a pair of RCK domains that assemble into an octameric gating ring on the intracellular side of the tetrameric channel.[8][11][12][13][14][15][16] The CTD contains four primary binding sites for Ca2+, called "calcium bowls", encoded within the second RCK domain of each monomer.[8][11][15][16]
Calcium-activated BK potassium channel alpha subunit
Identifiers
SymbolBK_channel_a
PfamPF03493
InterProIPR003929
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Available X-ray structures include:

  • 3U6N​ – Open structure of the BK channel gating ring[16]
  • 3MT5​ – Crystal structure of the human BK gating apparatus[8]
  • 3NAF​ – Structure of the intracellular gating ring from the human high-conductance Ca2+ gated K+ channel (BK Channel)[11]

Pharmacology

BK channels are pharmacological targets for the treatment of stroke. Various pharmaceutical companies developed synthetic molecules activating these channels[17] in order to prevent excessive neurotoxic calcium entry in neurons.[18] But BMS-204352 (MaxiPost) a molecule developed by Bristol-Myers Squibb failed to improve clinical outcome in stroke patients compared to placebo.[19] BK channels have also been found to be activated by exogenous pollutants and endogenous gasotransmitters carbon monoxide[20][21] and hydrogen sulphide.[22]

BK channels are blocked by tetraethylammonium (TEA), paxilline[23] and iberiotoxin.[24]

Researchers have identified a rare disease in humans caused by mutations in the gene.  KCNMA1-linked channelopathy can cause neurological conditions like seizures and movement disorders.[25] An episode of the Diagnosis TV show, based on a column in the New York Times, was about a young girl with a KCNMA1 disorder that caused transient episodes of muscle weakness.[26]

See also

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000156113 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000063142 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "HomoloGene - NCBI". www.ncbi.nlm.nih.gov.
  6. 1 2 3 "Entrez Gene: KCNMA1 potassium large conductance calcium-activated channel, subfamily M, alpha member 1".
  7. ↑ Miller C (2000). "An overview of the potassium channel family". Genome Biology. 1 (4): REVIEWS0004. doi:10.1186/gb-2000-1-4-reviews0004. PMC 138870. PMID 11178249.
  8. 1 2 3 4 Yuan P, Leonetti MD, Pico AR, Hsiung Y, MacKinnon R (July 2010). "Structure of the human BK channel Ca2+-activation apparatus at 3.0 A resolution". Science. 329 (5988): 182–6. Bibcode:2010Sci...329..182Y. doi:10.1126/science.1190414. PMC 3022345. PMID 20508092.
  9. ↑ Davies AG, Pierce-Shimomura JT, Kim H, VanHoven MK, Thiele TR, Bonci A, et al. (December 2003). "A central role of the BK potassium channel in behavioral responses to ethanol in C. elegans". Cell. 115 (6): 655–66. doi:10.1016/S0092-8674(03)00979-6. PMID 14675531. S2CID 8120562.
  10. ↑ Wallner M, Meera P, Toro L (December 1996). "Determinant for beta-subunit regulation in high-conductance voltage-activated and Ca(2+)-sensitive K+ channels: an additional transmembrane region at the N terminus". Proceedings of the National Academy of Sciences of the United States of America. 93 (25): 14922–7. Bibcode:1996PNAS...9314922W. doi:10.1073/pnas.93.25.14922. PMC 26238. PMID 8962157.
  11. 1 2 3 Wu Y, Yang Y, Ye S, Jiang Y (July 2010). "Structure of the gating ring from the human large-conductance Ca(2+)-gated K(+) channel". Nature. 466 (7304): 393–7. Bibcode:2010Natur.466..393W. doi:10.1038/nature09252. PMC 2910425. PMID 20574420.
  12. ↑ Jiang Y, Pico A, Cadene M, Chait BT, MacKinnon R (March 2001). "Structure of the RCK domain from the E. coli K+ channel and demonstration of its presence in the human BK channel". Neuron. 29 (3): 593–601. doi:10.1016/S0896-6273(01)00236-7. PMID 11301020. S2CID 17880955.
  13. ↑ Pico A. 2003. RCK domain model of calcium activation in BK channels. PhD thesis. The Rockfeller University, New York.
  14. ↑ Yusifov T, Savalli N, Gandhi CS, Ottolia M, Olcese R (January 2008). "The RCK2 domain of the human BKCa channel is a calcium sensor". Proceedings of the National Academy of Sciences of the United States of America. 105 (1): 376–81. Bibcode:2008PNAS..105..376Y. doi:10.1073/pnas.0705261105. PMC 2224220. PMID 18162557.
  15. 1 2 Schreiber M, Salkoff L (September 1997). "A novel calcium-sensing domain in the BK channel". Biophysical Journal. 73 (3): 1355–63. Bibcode:1997BpJ....73.1355S. doi:10.1016/S0006-3495(97)78168-2. PMC 1181035. PMID 9284303.
  16. 1 2 3 Yuan P, Leonetti MD, Hsiung Y, MacKinnon R (December 2011). "Open structure of the Ca2+ gating ring in the high-conductance Ca2+-activated K+ channel". Nature. 481 (7379): 94–7. Bibcode:2012Natur.481...94Y. doi:10.1038/nature10670. PMC 3319005. PMID 22139424.
  17. ↑ Gribkoff VK, Winquist RJ (May 2005). "Voltage-gated cation channel modulators for the treatment of stroke". Expert Opinion on Investigational Drugs. 14 (5): 579–92. doi:10.1517/13543784.14.5.579. PMID 15926865. S2CID 10236998.
  18. ↑ Gribkoff VK, Starrett JE, Dworetzky SI (April 2001). "Maxi-K potassium channels: form, function, and modulation of a class of endogenous regulators of intracellular calcium". The Neuroscientist. 7 (2): 166–77. doi:10.1177/107385840100700211. PMID 11496927. S2CID 8791803.
  19. ↑ Jensen BS (2002). "BMS-204352: a potassium channel opener developed for the treatment of stroke". CNS Drug Reviews. 8 (4): 353–60. doi:10.1111/j.1527-3458.2002.tb00233.x. PMC 6741660. PMID 12481191.
  20. ↑ Dubuis E, Potier M, Wang R, Vandier C (February 2005). "Continuous inhalation of carbon monoxide attenuates hypoxic pulmonary hypertension development presumably through activation of BKCa channels". Cardiovascular Research. 65 (3): 751–61. doi:10.1016/j.cardiores.2004.11.007. PMID 15664403.
  21. ↑ Hou S, Xu R, Heinemann SH, Hoshi T (March 2008). "The RCK1 high-affinity Ca2+ sensor confers carbon monoxide sensitivity to Slo1 BK channels". Proceedings of the National Academy of Sciences of the United States of America. 105 (10): 4039–43. Bibcode:2008PNAS..105.4039H. doi:10.1073/pnas.0800304105. PMC 2268785. PMID 18316727.
  22. ↑ Sitdikova GF, Weiger TM, Hermann A (February 2010). "Hydrogen sulfide increases calcium-activated potassium (BK) channel activity of rat pituitary tumor cells". Pflügers Archiv. 459 (3): 389–97. doi:10.1007/s00424-009-0737-0. PMID 19802723. S2CID 23073556.
  23. ↑ "Paxilline, from Fermentek".
  24. ↑ Candia S, Garcia ML, Latorre R (August 1992). "Mode of action of iberiotoxin, a potent blocker of the large conductance Ca(2+)-activated K+ channel". Biophysical Journal. 63 (2): 583–90. Bibcode:1992BpJ....63..583C. doi:10.1016/S0006-3495(92)81630-2. PMC 1262182. PMID 1384740.
  25. ↑ Bailey CS, Moldenhauer HJ, Park SM, Keros S, Meredith AL (October 2019). "KCNMA1-linked channelopathy". The Journal of General Physiology. 151 (10): 1173–1189. doi:10.1085/jgp.201912457. PMC 6785733. PMID 31427379.
  26. ↑ Sanders L (2018-09-11). "A Diagnosis Update: New Information on a Young Girl's Rare Genetic Condition". The New York Times. Retrieved 2019-11-02.

Further reading

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