Calcium-activated potassium channel subunit alpha-1 explained

Calcium-activated potassium channel subunit alpha-1 also known as large conductance calcium-activated potassium channel, subfamily M, alpha member 1 (K_Ca1.1), or BK channel alpha subunit,^[1] is a voltage gated potassium channel encoded by the KCNMA1 gene and characterized by their large conductance of potassium ions (K+) through cell membranes.^[2]

Function

BK channels are activated (opened) by changes in membrane electrical potential and/or by increases in concentration of intracellular calcium ion (Ca²⁺).^{[3] [4]} 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. 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).^[5] 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.^[2]

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

1. A unique transmembrane domain (S0)^[6] 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.^{[7] [8] [9] [10] [11]} The CTD contains four primary binding sites for Ca²⁺, called "calcium bowls", encoded within the second RCK domain of each monomer.^{[4] [7] [11]}

Available X-ray structures include:

• – Open structure of the BK channel gating ring^[12]
• – Crystal structure of the human BK gating apparatus^[4]
• – Structure of the intracellular gating ring from the human high-conductance Ca²⁺ gated K⁺ channel (BK Channel)^[7]

Pharmacology

BK channels are pharmacological targets for the treatment of stroke. Various pharmaceutical companies developed synthetic molecules activating these channels^[13] in order to prevent excessive neurotoxic calcium entry in neurons.^[14] But BMS-204352 (MaxiPost) a molecule developed by Bristol-Myers Squibb failed to improve clinical outcome in stroke patients compared to placebo.^[15] BK channels have also been found to be activated by exogenous pollutants and endogenous gasotransmitters carbon monoxide^{[16] [17]} and hydrogen sulphide.^[18]

BK channels are blocked by tetraethylammonium (TEA), paxilline^[19] and iberiotoxin.^[20]

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.^[21] 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.^[22]

See also

• BK channel
• Calcium-activated potassium channel
• Voltage-gated potassium channel

Further reading

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

External links

• Meredith Lab

Notes and References

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