View source for Calcium-activated potassium channel subunit alpha-1

{{short description|Voltage-gated potassium channel protein}}
{{Infobox_gene}}
'''Calcium-activated potassium channel subunit alpha-1''' also known as  '''large conductance calcium-activated potassium channel, subfamily M, alpha member 1''' (K<sub>Ca</sub>1.1), or '''BK channel alpha subunit''',<ref name="NCBI">{{cite web |title=HomoloGene - NCBI |url=https://www.ncbi.nlm.nih.gov/homologene?cmd=Retrieve&dopt=HomoloGene&list_uids=1693 |website=www.ncbi.nlm.nih.gov}}</ref> is a voltage gated [[potassium channel]] encoded by the '''KCNMA1''' [[gene]] and characterized by their large conductance of [[potassium]] ions (K+) through [[cell membranes]].<ref name="entrez">{{cite web | title = Entrez Gene: KCNMA1 potassium large conductance calcium-activated channel, subfamily M, alpha member 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3778}}</ref>

== Function ==

[[BK channel]]s are activated (opened) by changes in [[membrane potential|membrane electrical potential]] and/or by increases in concentration of [[intracellular]] [[calcium]] ion (Ca<sup>2+</sup>).<ref name="pmid11178249">{{cite journal | vauthors = Miller C | title = An overview of the potassium channel family | journal = Genome Biology | volume = 1 | issue = 4 | pages = REVIEWS0004 | year = 2000 | pmid = 11178249 | pmc = 138870 | doi = 10.1186/gb-2000-1-4-reviews0004 | doi-access = free }}</ref><ref name="pmid20508092">{{cite journal | vauthors = Yuan P, Leonetti MD, Pico AR, Hsiung Y, MacKinnon R | title = Structure of the human BK channel Ca2+-activation apparatus at 3.0 A resolution | journal = Science | volume = 329 | issue = 5988 | pages = 182–6 | date = July 2010 | pmid = 20508092 | pmc = 3022345 | doi = 10.1126/science.1190414 | bibcode = 2010Sci...329..182Y }}</ref> Opening of BK channels allows K<sup>+</sup> to passively flow through the channel, down the [[electrochemical gradient]]. Under typical physiological conditions, this results in an efflux of K<sup>+</sup> from the cell, which leads to cell membrane [[hyperpolarization (biology)|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]] [[muscle tone|tone]] and neuronal excitability.<ref name="entrez" /> They control the contraction of smooth muscle and are involved with the [[electrical tuning]] of [[hair cell]]s in the [[cochlea]]. BK channels also contribute to the behavioral effects of [[ethanol]] in the worm ''[[Caenorhabditis elegans|C. elegans]]'' under high concentrations (> 100 mM, or approximately 0.50% BAC).<ref name="pmid14675531">{{cite journal | vauthors = Davies AG, Pierce-Shimomura JT, Kim H, VanHoven MK, Thiele TR, Bonci A, Bargmann CI, McIntire SL | display-authors = 6 | title = A central role of the BK potassium channel in behavioral responses to ethanol in C. elegans | journal = Cell | volume = 115 | issue = 6 | pages = 655–66 | date = December 2003 | pmid = 14675531 | doi = 10.1016/S0092-8674(03)00979-6 | s2cid = 8120562 | doi-access = free }}</ref> 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.<ref name="entrez"/>

Each BK channel alpha subunit consists of (from N- to C-terminal):
#A unique [[transmembrane domain]] (S0)<ref name="pmid8962157">{{cite journal | vauthors = Wallner M, Meera P, Toro L | title = Determinant for beta-subunit regulation in high-conductance voltage-activated and Ca(2+)-sensitive K+ channels: an additional transmembrane region at the N terminus | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 25 | pages = 14922–7 | date = December 1996 | pmid = 8962157 | pmc = 26238 | doi = 10.1073/pnas.93.25.14922 | bibcode = 1996PNAS...9314922W | doi-access = free }}</ref> that precedes the 6 transmembrane domains (S1-S6) conserved in all voltage-dependent K<sup>+</sup> channels.
#A voltage sensing domain (S1-S4).
#A K<sup>+</sup> channel pore domain (S5, selectivity filter, and S6).
#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.<ref name="pmid20508092" /><ref name="pmid20574420">{{cite journal | vauthors = Wu Y, Yang Y, Ye S, Jiang Y | title = Structure of the gating ring from the human large-conductance Ca(2+)-gated K(+) channel | journal = Nature | volume = 466 | issue = 7304 | pages = 393–7 | date = July 2010 | pmid = 20574420 | pmc = 2910425 | doi = 10.1038/nature09252 | bibcode = 2010Natur.466..393W }}</ref><ref name="pmid11301020">{{cite journal | vauthors = Jiang Y, Pico A, Cadene M, Chait BT, MacKinnon R | title = Structure of the RCK domain from the E. coli K+ channel and demonstration of its presence in the human BK channel | journal = Neuron | volume = 29 | issue = 3 | pages = 593–601 | date = March 2001 | pmid = 11301020 | doi = 10.1016/S0896-6273(01)00236-7 | s2cid = 17880955 | doi-access = free }}</ref><ref>Pico A. 2003. RCK domain model of calcium activation in BK channels. PhD thesis. The Rockfeller University, New York.</ref><ref name="pmid18162557">{{cite journal | vauthors = Yusifov T, Savalli N, Gandhi CS, Ottolia M, Olcese R | title = The RCK2 domain of the human BKCa channel is a calcium sensor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 1 | pages = 376–81 | date = January 2008 | pmid = 18162557 | pmc = 2224220 | doi = 10.1073/pnas.0705261105 | bibcode = 2008PNAS..105..376Y | doi-access = free }}</ref><ref name="pmid9284303">{{cite journal | vauthors = Schreiber M, Salkoff L | title = A novel calcium-sensing domain in the BK channel | journal = Biophysical Journal | volume = 73 | issue = 3 | pages = 1355–63 | date = September 1997 | pmid = 9284303 | pmc = 1181035 | doi = 10.1016/S0006-3495(97)78168-2 | bibcode = 1997BpJ....73.1355S }}</ref><ref name="pmid22139424"/> The CTD contains four primary binding sites for Ca<sup>2+</sup>, called "calcium bowls", encoded within the second RCK domain of each monomer.<ref name="pmid20508092"/><ref name="pmid20574420"/><ref name="pmid9284303"/><ref name="pmid22139424"/>

{{stack|{{Infobox protein family
| Symbol = BK_channel_a
| Name = Calcium-activated BK potassium channel alpha subunit
| image = 
| width = 
| caption = 
| Pfam = PF03493
| Pfam_clan =  
| InterPro = IPR003929
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}}}

Available X-ray structures include:
* {{PDB2|3U6N}} – Open structure of the BK channel gating ring<ref name="pmid22139424">{{cite journal | vauthors = Yuan P, Leonetti MD, Hsiung Y, MacKinnon R | title = Open structure of the Ca2+ gating ring in the high-conductance Ca2+-activated K+ channel | journal = Nature | volume = 481 | issue = 7379 | pages = 94–7 | date = December 2011 | pmid = 22139424 | pmc = 3319005 | doi = 10.1038/nature10670 | bibcode = 2012Natur.481...94Y }}</ref>
* {{PDB2|3MT5}} – Crystal structure of the human BK gating apparatus<ref name="pmid20508092"/>
* {{PDB2|3NAF}} – Structure of the intracellular gating ring from the human high-conductance Ca<sup>2+</sup> gated K<sup>+</sup> channel (BK Channel)<ref name="pmid20574420"/>

==Pharmacology==
BK channels are pharmacological targets for the treatment of stroke. Various pharmaceutical companies developed synthetic molecules activating these channels<ref name="pmid15926865">{{cite journal | vauthors = Gribkoff VK, Winquist RJ | title = Voltage-gated cation channel modulators for the treatment of stroke | journal = Expert Opinion on Investigational Drugs | volume = 14 | issue = 5 | pages = 579–92 | date = May 2005 | pmid = 15926865 | doi = 10.1517/13543784.14.5.579 | s2cid = 10236998 }}</ref> in order to prevent excessive [[neurotoxic]] calcium entry in neurons.<ref name="pmid11496927">{{cite journal | vauthors = Gribkoff VK, Starrett JE, Dworetzky SI | title = Maxi-K potassium channels: form, function, and modulation of a class of endogenous regulators of intracellular calcium | journal = The Neuroscientist | volume = 7 | issue = 2 | pages = 166–77 | date = April 2001 | pmid = 11496927 | doi = 10.1177/107385840100700211 | s2cid = 8791803 }}</ref> But BMS-204352 (MaxiPost) a molecule developed by [[Bristol-Myers Squibb]] failed to improve clinical outcome in stroke patients compared to [[placebo]].<ref name="pmid12481191">{{cite journal | vauthors = Jensen BS | title = BMS-204352: a potassium channel opener developed for the treatment of stroke | journal = CNS Drug Reviews | volume = 8 | issue = 4 | pages = 353–60 | year = 2002 | pmid = 12481191 | pmc = 6741660 | doi = 10.1111/j.1527-3458.2002.tb00233.x }}</ref> BK channels have also been found to be activated by exogenous pollutants and endogenous gasotransmitters carbon monoxide<ref name="pmid15664403">{{cite journal | vauthors = Dubuis E, Potier M, Wang R, Vandier C | title = Continuous inhalation of carbon monoxide attenuates hypoxic pulmonary hypertension development presumably through activation of BKCa channels | journal = Cardiovascular Research | volume = 65 | issue = 3 | pages = 751–61 | date = February 2005 | pmid = 15664403 | doi = 10.1016/j.cardiores.2004.11.007 | doi-access = free }}</ref><ref name="pmid18316727">{{cite journal | vauthors = Hou S, Xu R, Heinemann SH, Hoshi T | title = The RCK1 high-affinity Ca2+ sensor confers carbon monoxide sensitivity to Slo1 BK channels | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 10 | pages = 4039–43 | date = March 2008 | pmid = 18316727 | pmc = 2268785 | doi = 10.1073/pnas.0800304105 | bibcode = 2008PNAS..105.4039H | doi-access = free }}</ref> and hydrogen sulphide.<ref name="pmid19802723">{{cite journal | vauthors = Sitdikova GF, Weiger TM, Hermann A | title = Hydrogen sulfide increases calcium-activated potassium (BK) channel activity of rat pituitary tumor cells | journal = Pflügers Archiv | volume = 459 | issue = 3 | pages = 389–97 | date = February 2010 | pmid = 19802723 | doi = 10.1007/s00424-009-0737-0 | s2cid = 23073556 }}</ref>

BK channels are blocked by tetraethylammonium (TEA), [[paxilline]]<ref name="urlpaxilline, pure, from Fermentek">{{cite web |url=http://www.fermentek.com/product/paxilline| title = Paxilline, from Fermentek | date = January 2005 }}</ref> and [[iberiotoxin]].<ref name="pmid1384740">{{cite journal | vauthors = Candia S, Garcia ML, Latorre R | title = Mode of action of iberiotoxin, a potent blocker of the large conductance Ca(2+)-activated K+ channel | journal = Biophysical Journal | volume = 63 | issue = 2 | pages = 583–90 | date = August 1992 | pmid = 1384740 | pmc = 1262182 | doi = 10.1016/S0006-3495(92)81630-2 | bibcode = 1992BpJ....63..583C }}</ref>

==Related conditions==

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.<ref>{{cite journal | vauthors = Bailey CS, Moldenhauer HJ, Park SM, Keros S, Meredith AL | title = KCNMA1-linked channelopathy | journal = The Journal of General Physiology | volume = 151 | issue = 10 | pages = 1173–1189 | date = October 2019 | pmid = 31427379 | pmc = 6785733 | doi = 10.1085/jgp.201912457 }}</ref> An episode of the [[Diagnosis (American TV series)|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.<ref>{{Cite news|url=https://www.nytimes.com/2018/09/11/magazine/a-diagnosis-update-new-information-on-a-young-girls-rare-genetic-condition.html |title=A Diagnosis Update: New Information on a Young Girl's Rare Genetic Condition |last=Sanders |first=Lisa | name-list-style = vanc |date=2018-09-11|work=The New York Times |access-date=2019-11-02 }}</ref>

== See also ==
* [[BK channel]]
* [[Calcium-activated potassium channel]]
* [[Voltage-gated potassium channel]]

== References ==
{{reflist|32em}}

== Further reading ==
{{refbegin|32em}}
* {{cite journal | vauthors = Magleby KL | title = Gating mechanism of BK (Slo1) channels: so near, yet so far | journal = The Journal of General Physiology | volume = 121 | issue = 2 | pages = 81–96 | date = February 2003 | pmid = 12566537 | pmc = 2217328 | doi = 10.1085/jgp.20028721 }}
* {{cite journal | vauthors = Wei AD, Gutman GA, Aldrich R, Chandy KG, Grissmer S, Wulff H | title = International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium-activated potassium channels | journal = Pharmacological Reviews | volume = 57 | issue = 4 | pages = 463–72 | date = December 2005 | pmid = 16382103 | doi = 10.1124/pr.57.4.9 | s2cid = 8290401 }}
* {{cite journal | vauthors = McCobb DP, Fowler NL, Featherstone T, Lingle CJ, Saito M, Krause JE, Salkoff L | title = A human calcium-activated potassium channel gene expressed in vascular smooth muscle | journal = The American Journal of Physiology | volume = 269 | issue = 3 Pt 2 | pages = H767-77 | date = September 1995 | pmid = 7573516 | doi = 10.1152/ajpheart.1995.269.3.H767 }}
* {{cite journal | vauthors = Butler A, Tsunoda S, McCobb DP, Wei A, Salkoff L | title = mSlo, a complex mouse gene encoding "maxi" calcium-activated potassium channels | journal = Science | volume = 261 | issue = 5118 | pages = 221–4 | date = July 1993 | pmid = 7687074 | doi = 10.1126/science.7687074 | bibcode = 1993Sci...261..221B }}
* {{cite journal | vauthors = Dworetzky SI, Trojnacki JT, Gribkoff VK | title = Cloning and expression of a human large-conductance calcium-activated potassium channel | journal = Brain Research. Molecular Brain Research | volume = 27 | issue = 1 | pages = 189–93 | date = November 1994 | pmid = 7877450 | doi = 10.1016/0169-328X(94)90203-8 }}
* {{cite journal | vauthors = Pallanck L, Ganetzky B | title = Cloning and characterization of human and mouse homologs of the Drosophila calcium-activated potassium channel gene, slowpoke | journal = Human Molecular Genetics | volume = 3 | issue = 8 | pages = 1239–43 | date = August 1994 | pmid = 7987297 | doi = 10.1093/hmg/3.8.1239 }}
* {{cite journal | vauthors = Tseng-Crank J, Foster CD, Krause JD, Mertz R, Godinot N, DiChiara TJ, Reinhart PH | title = Cloning, expression, and distribution of functionally distinct Ca(2+)-activated K+ channel isoforms from human brain | journal = Neuron | volume = 13 | issue = 6 | pages = 1315–30 | date = December 1994 | pmid = 7993625 | doi = 10.1016/0896-6273(94)90418-9 | s2cid = 31170819 }}
* {{cite journal | vauthors = Knaus HG, Folander K, Garcia-Calvo M, Garcia ML, Kaczorowski GJ, Smith M, Swanson R | title = Primary sequence and immunological characterization of beta-subunit of high conductance Ca(2+)-activated K+ channel from smooth muscle | journal = The Journal of Biological Chemistry | volume = 269 | issue = 25 | pages = 17274–8 | date = June 1994 | doi = 10.1016/S0021-9258(17)32551-6 | pmid = 8006036 | doi-access = free }}
* {{cite journal | vauthors = Meera P, Wallner M, Jiang Z, Toro L | title = A calcium switch for the functional coupling between alpha (hslo) and beta subunits (KV,Ca beta) of maxi K channels | journal = FEBS Letters | volume = 382 | issue = 1–2 | pages = 84–8 | date = March 1996 | pmid = 8612769 | doi = 10.1016/0014-5793(96)00151-2 | s2cid = 81684849 | doi-access = free | bibcode = 1996FEBSL.382...84M }}
* {{cite journal | vauthors = Wallner M, Meera P, Ottolia M, Kaczorowski GJ, Latorre R, Garcia ML, Stefani E, Toro L | display-authors = 6 | title = Characterization of and modulation by a beta-subunit of a human maxi KCa channel cloned from myometrium | journal = Receptors & Channels | volume = 3 | issue = 3 | pages = 185–99 | year = 1996 | pmid = 8821792 }}
* {{cite journal | vauthors = Meera P, Wallner M, Song M, Toro L | title = Large conductance voltage- and calcium-dependent K+ channel, a distinct member of voltage-dependent ion channels with seven N-terminal transmembrane segments (S0-S6), an extracellular N terminus, and an intracellular (S9-S10) C terminus | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 25 | pages = 14066–71 | date = December 1997 | pmid = 9391153 | pmc = 28433 | doi = 10.1073/pnas.94.25.14066 | bibcode = 1997PNAS...9414066M | doi-access = free }}
* {{cite journal | vauthors = Díaz L, Meera P, Amigo J, Stefani E, Alvarez O, Toro L, Latorre R | title = Role of the S4 segment in a voltage-dependent calcium-sensitive potassium (hSlo) channel | journal = The Journal of Biological Chemistry | volume = 273 | issue = 49 | pages = 32430–6 | date = December 1998 | pmid = 9829973 | doi = 10.1074/jbc.273.49.32430 | doi-access = free }}
* {{cite journal | vauthors = Wallner M, Meera P, Toro L | title = Molecular basis of fast inactivation in voltage and Ca2+-activated K+ channels: a transmembrane beta-subunit homolog | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 7 | pages = 4137–42 | date = March 1999 | pmid = 10097176 | pmc = 22433 | doi = 10.1073/pnas.96.7.4137 | bibcode = 1999PNAS...96.4137W | doi-access = free }}
* {{cite journal | vauthors = Valverde MA, Rojas P, Amigo J, Cosmelli D, Orio P, Bahamonde MI, Mann GE, Vergara C, Latorre R | display-authors = 6 | title = Acute activation of Maxi-K channels (hSlo) by estradiol binding to the beta subunit | journal = Science | volume = 285 | issue = 5435 | pages = 1929–31 | date = September 1999 | pmid = 10489376 | doi = 10.1126/science.285.5435.1929 }}
* {{cite journal | vauthors = Brenner R, Jegla TJ, Wickenden A, Liu Y, Aldrich RW | title = Cloning and functional characterization of novel large conductance calcium-activated potassium channel beta subunits, hKCNMB3 and hKCNMB4 | journal = The Journal of Biological Chemistry | volume = 275 | issue = 9 | pages = 6453–61 | date = March 2000 | pmid = 10692449 | doi = 10.1074/jbc.275.9.6453 | doi-access = free }}
* {{cite journal | vauthors = Liu QH, Williams DA, McManus C, Baribaud F, Doms RW, Schols D, De Clercq E, Kotlikoff MI, Collman RG, Freedman BD | display-authors = 6 | title = HIV-1 gp120 and chemokines activate ion channels in primary macrophages through CCR5 and CXCR4 stimulation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 9 | pages = 4832–7 | date = April 2000 | pmid = 10758170 | pmc = 18318 | doi = 10.1073/pnas.090521697 | bibcode = 2000PNAS...97.4832L | doi-access = free }}
* {{cite journal | vauthors = Quirk JC, Reinhart PH | title = Identification of a novel tetramerization domain in large conductance K(ca) channels | journal = Neuron | volume = 32 | issue = 1 | pages = 13–23 | date = October 2001 | pmid = 11604135 | doi = 10.1016/S0896-6273(01)00444-5 | s2cid = 18208592 | doi-access = free }}
* {{cite journal | vauthors = Soto MA, González C, Lissi E, Vergara C, Latorre R | title = Ca(2+)-activated K+ channel inhibition by reactive oxygen species | journal = American Journal of Physiology. Cell Physiology | volume = 282 | issue = 3 | pages = C461-71 | date = March 2002 | pmid = 11832330 | doi = 10.1152/ajpcell.00167.2001 | hdl = 10533/172864 | hdl-access = free }}
* {{cite journal | vauthors = Wang YW, Ding JP, Xia XM, Lingle CJ | title = Consequences of the stoichiometry of Slo1 alpha and auxiliary beta subunits on functional properties of large-conductance Ca2+-activated K+ channels | journal = The Journal of Neuroscience | volume = 22 | issue = 5 | pages = 1550–61 | date = March 2002 | pmid = 11880485 | pmc = 6758889 | doi = 10.1523/JNEUROSCI.22-05-01550.2002 }}
{{refend}}

== External links ==
{{Medical condition classification and resources
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* [https://meredithlab.org/ Meredith Lab]

[[Category:Ion channels]]