Calcium-activated potassium channel subunit alpha-1

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Potassium large conductance calcium-activated channel, subfamily M, alpha member 1
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols KCNMA1 ; BKTM; KCa1.1; MaxiK; SAKCA; SLO; SLO-ALPHA; SLO1; bA205K10.1; mSLO1
External IDs OMIM600150 MGI99923 HomoloGene1693 IUPHAR: KCa1.1 ChEMBL: 4304 GeneCards: KCNMA1 Gene
RNA expression pattern
PBB GE KCNMA1 221583 s at tn.png
PBB GE KCNMA1 221584 s at tn.png
PBB GE KCNMA1 214921 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 3778 16531
Ensembl ENSG00000156113 ENSMUSG00000063142
UniProt Q12791 Q08460
RefSeq (mRNA) NM_001014797 NM_001253358
RefSeq (protein) NP_001014797 NP_001240287
Location (UCSC) Chr 10:
78.64 – 79.4 Mb
Chr 14:
23.29 – 23.8 Mb
PubMed search [1] [2]

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 for short, is a voltage gated potassium channel encoded by the KCNMA1 gene and characterized by their large conductance of potassium ions (K+) through cell membranes.1

Function

BK channels are activated (opened) by changes in membrane electrical potential and/or by increases in concentration of intracellular calcium ion (Ca2+).23 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.1 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).4 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 tetrametic channel. Alternatively spliced transcript variants encoding different isoforms have been identified.1

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

  1. A unique transmembrane domain (S0)5 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.367891011 The CTD contains four primary binding sites for Ca2+, called "calcium bowls", encoded within the second RCK domain of each monomer.361011
Calcium-activated BK potassium channel alpha subunit
Identifiers
Symbol BK_channel_a
Pfam PF03493
InterPro IPR003929

Available X-ray structures include:

  • 3U6N – Open structure of the BK channel gating ring11
  • 3MT5 – Crystal structure of the human BK gating apparatus3
  • 3NAF – Structure of the intracellular gating ring from the human high-conductance Ca2+ gated K+ channel (BK Channel)6

Pharmacology

BK channels are pharmacological targets for the treatment of stroke. Various pharmaceutical companies developed synthetic molecules activating these channels12 in order to prevent excessive neurotoxic calcium entry in neurons.13 But BMS-204352 (MaxiPost) a molecule developed by Bristol-Myers Squibb failed to improve clinical outcome in stroke patients compared to placebo.14 BK channels have also been found to be activated by exogenous pollutants and endogenous gazotransmitters carbon monoxide1516 and hydrogen sulphide.17

BK channels are blocked by tetraethylammonium (TEA), paxilline18 and iberiotoxin.19

See also

References

  1. ^ a b c "Entrez Gene: KCNMA1 potassium large conductance calcium-activated channel, subfamily M, alpha member 1". 
  2. ^ Miller C (2000). "An overview of the potassium channel family". Genome Biol. 1 (4): reviews0004.1–reviews0004.5. doi:10.1186/gb-2000-1-4-reviews0004. PMC 138870. PMID 11178249. 
  3. ^ a b c d 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. 
  4. ^ Davies AG, Pierce-Shimomura JT, Kim H, VanHoven MK, Thiele TR, Bonci A, Bargmann CI, McIntire SL (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. 
  5. ^ Wallner M, Meera P, Toro L (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.  
  6. ^ a b c Wu Y, Yang Y, Ye S, Jiang Y (2010). "Structure of the gating ring from the human large-conductance Ca2+-gated K+ channel". Nature 466 (7304): 393–397. Bibcode:2010Natur.466..393W. doi:10.1038/nature09252. PMC 2910425. PMID 20574420.  
  7. ^ Jiang Y, Pico A, Cadene M, Chait BT, MacKinnon R. (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.  
  8. ^ Pico A. 2003. RCK domain model of calcium activation in BK channels. PhD thesis. The Rockfeller University, New York.
  9. ^ Yusifov T, Savalli N, Gandhi CS, Ottolia M, Olcese R (2008). "The RCK2 domain of the human BKCa channel is a calcium sensor". Proceedings of the National Academy of Sciences 105 (1): 376–81. Bibcode:2008PNAS..105..376Y. doi:10.1073/pnas.0705261105. PMC 2224220. PMID 18162557.  
  10. ^ a b Schreiber M, Salkoff L (1997). "A novel calcium-sensing domain in the BK channel". Biophysical Journal 73 (3): 1355–1363. Bibcode:1997BpJ....73.1355S. doi:10.1016/S0006-3495(97)78168-2. PMC 1181035. PMID 9284303.  
  11. ^ a b c Yuan P, Leonetti MD, Hsiung Y, MacKinnon R (2011). "Open structure of the Ca2+ gating ring in the high-conductance Ca2+-activated K+ channel". Nature 481 (7379): 94–97. doi:10.1038/nature10670. PMC 3319005. PMID 22139424.  
  12. ^ Gribkoff VK, Winquist RJ (May 2005). "Voltage-gated cation channel modulators for the treatment of stroke". Expert Opin Investig Drugs 14 (5): 579–92. doi:10.1517/13543784.14.5.579. PMID 15926865. 
  13. ^ 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". Neuroscientist 7 (2): 166–77. doi:10.1177/107385840100700211. PMID 11496927. 
  14. ^ Jensen BS (2002). "BMS-204352: a potassium channel opener developed for the treatment of stroke". CNS Drug Rev 8 (4): 353–60. doi:10.1111/j.1527-3458.2002.tb00233.x. PMID 12481191. 
  15. ^ 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". Cardiovasc. Res. 65 (3): 751–61. doi:10.1016/j.cardiores.2004.11.007. PMID 15664403. 
  16. ^ Hou S, Xu R, Heinemann SH, Hoshi T (March 2008). "The RCK1 high-affinity Ca2+ sensor confers carbon monoxide sensitivity to Slo1 BK channels". Proc. Natl. Acad. Sci. U.S.A. 105 (10): 4039–43. Bibcode:2008PNAS..105.4039H. doi:10.1073/pnas.0800304105. PMC 2268785. PMID 18316727. 
  17. ^ Sitdikova GF, Weiger TM, Hermann A (February 2010). "Hydrogen sulfide increases calcium-activated potassium (BK) channel activity of rat pituitary tumor cells". Pflugers Arch. 459 (3): 389–97. doi:10.1007/s00424-009-0737-0. PMID 19802723. 
  18. ^ "Paxilline, from Fermentek". 
  19. ^ 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". Biophys. J. 63 (2): 583–90. Bibcode:1992BpJ....63..583C. doi:10.1016/S0006-3495(92)81630-2. PMC 1262182. PMID 1384740. 

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.








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