BK channel

KCNMA1
The domain structure of BK channels
Identifiers
Symbol	KCNMA1
Alt. symbols	SLO
Entrez	3778
HUGO	6284
OMIM	600150
RefSeq	NM_002247
UniProt	Q12791
Other data
Locus	Chr. 10 q22

KCNMB1
Identifiers
Symbol	KCNMB1
Entrez	3779
HUGO	6285
OMIM	603951
RefSeq	NM_004137
UniProt	Q16558
Other data
Locus	Chr. 5 q34

KCNMB2
Identifiers
Symbol	KCNMB2
Entrez	10242
HUGO	6286
OMIM	605214
RefSeq	NM_181361
UniProt	Q9Y691
Other data
Locus	Chr. 3 q26.32

KCNMB3
Identifiers
Symbol	KCNMB3
Alt. symbols	KCNMB2, KCNMBL
Entrez	27094
HUGO	6287
OMIM	605222
RefSeq	NM_171828
UniProt	Q9NPA1
Other data
Locus	Chr. 3 q26.3-q27

KCNMB3L
Identifiers
Symbol	KCNMB3L
Alt. symbols	KCNMB2L, KCNMBLP
Entrez	27093
HUGO	6288
RefSeq	NG_002679
Other data
Locus	Chr. 22 q11.1

KCNMB4
Identifiers
Symbol	KCNMB4
Entrez	27345
HUGO	6289
OMIM	605223
RefSeq	NM_014505
UniProt	Q86W47
Other data
Locus	Chr. 12 q15

Calcium-activated BK potassium channel alpha subunit
Identifiers
Symbol	BK_channel_a
Pfam	PF03493
InterPro	IPR003929
Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary

BK channels (Big Potassium), also called Maxi-K or slo1, are ion channels characterized by their large conductance of potassium ions (K⁺) through cell membranes. These channels are activated (opened) by changes in membrane electrical potential and/or by increases in concentration of intracellular calcium ion (Ca²⁺).^[1][2] 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.^[3] 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

As with other potassium channels, 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.

BK channels are a prime example of modular protein evolution. 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.^{[2][6][7][8][9][10]} The CTD contains four primary binding sites for Ca²⁺, called "calcium bowls", encoded within the second RCK domain of each monomer.^[2][6][10]

Available X-ray structures:

• 3MT5 - Crystal Structure of the Human BK Gating Apparatus^[2]
• 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 channels^[11] in order to prevent excessive neurotoxic calcium entry in neurons.^[12] But BMS-204352 (MaxiPost) a molecule developed by Bristol-Myers Squibb failed to improve clinical outcome in stroke patients compared to placebo.^[13] BK channels have also been found to be activated by exogenous pollutants and endogenous gazotransmitters carbon monoxide ^[14][15] and hydrogen sulphide.^[16]

BK channels are blocked by tetraethylammonium (TEA), paxilline^[17] and iberiotoxin.^[18]

See also

• Calcium-activated potassium channel

References

1. ^ Miller, C (2000). "An overview of the potassium channel family". Genome biology 1 (4): reviews0004.1–reviews0004.5. doi:10.1186/gb-2000-1-4-reviews0004. PMC 138870. PMID 11178249. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=138870. 
2. ^ ^{a b c d} Yuan, P.; Leonetti, M. D.; Pico, A. R.; Hsiung, Y.; MacKinnon, R. (2010). "Structure of the Human BK Channel Ca2+-Activation Apparatus at 3.0 Å Resolution". Science 329 (5988): 182–6. doi:10.1126/science.1190414. PMC 3022345. PMID 20508092. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3022345. 
3. ^ EntrezGene 3778
4. ^ Davies, Andrew G.; Pierce-Shimomura, Jonathan T.; Kim, Hongkyun; Vanhoven, Miri K.; Thiele, Tod R.; Bonci, Antonello; Bargmann, Cornelia I.; McIntire, Steven L. (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 β-subunit regulation in high-conductance voltage-activated and Ca2+-sensitive K+ channels: An additional transmembrane region at the N terminus". Proceedings of the National Academy of Sciences 93 (25): 14922–7. doi:10.1073/pnas.93.25.14922. PMC 26238. PMID 8962157. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=26238. 
6. ^ ^{a b c} Wu, Yunkun; Yang, Yi; Ye, Sheng; Jiang, Youxing (2010). "Structure of the Gating Ring from the Human High-conductance Ca2+-gated K+ Channel". Nature 466 (7304): 393–7. doi:10.1038/nature09252. PMC 2910425. PMID 20574420. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2910425. 
7. ^ Jiang, Youxing; Pico, Alexander; Cadene, Martine; Chait, Brian T.; MacKinnon, Roderick (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, Alexander R. (2003). RCK domain model of calcium activation in BK channels (PhD thesis). New York: The Rockfeller University. http://hdl.handle.net/10209/211. 
9. ^ Yusifov, T.; Savalli, N.; Gandhi, C. S.; 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. doi:10.1073/pnas.0705261105. PMC 2224220. PMID 18162557. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2224220. 
10. ^ ^{a b} Schreiber, M; Salkoff, L (1997). "A novel calcium-sensing domain in the BK channel". Biophysical Journal 73 (3): 1355–63. doi:10.1016/S0006-3495(97)78168-2. PMC 1181035. PMID 9284303. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1181035. 
11. ^ Gribkoff, Valentin K; Winquist, Raymond J (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. 
12. ^ Gribkoff, V. K.; Starrett, J. E.; Dworetzky, S. I. (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. 
13. ^ Jensen, Bo Skaaning (2006). "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. PMID 12481191. 
14. ^ Dubuis, E; Potier, M; Wang, R; Vandier, C (2005). "Continuous inhalation of carbon monoxide attenuates hypoxic pulmonary hypertension development presumably through activation of BK channels". Cardiovascular Research 65 (3): 751–61. doi:10.1016/j.cardiores.2004.11.007. PMID 15664403. 
15. ^ Hou, S.; Xu, R.; Heinemann, S. H.; Hoshi, T. (2008). "The RCK1 high-affinity Ca2+ sensor confers carbon monoxide sensitivity to Slo1 BK channels". Proceedings of the National Academy of Sciences 105 (10): 4039–43. doi:10.1073/pnas.0800304105. JSTOR 25461362. 
16. ^ Sitdikova, Guzel F.; Weiger, Thomas M.; Hermann, Anton (2009). "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. 
17. ^ "Paxilline, from Fermentek". http://www.fermentek.co.il/paxilline.htm. 
18. ^ Candia, S; Garcia, M; Latorre, R (1992). "Mode of action of iberiotoxin, a potent blocker of the large conductance Ca(2+)-activated K+ channel". Biophysical Journal 63 (2): 583–90. doi:10.1016/S0006-3495(92)81630-2. PMC 1262182. PMID 1384740. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1262182. 

External links

• MeSH BK+Channels
• Potassium Channels
• "Calcium-Activated Potassium Channels: K_Ca1.1". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/IC/ObjectDisplayForward?familyId=15&objectId=67.