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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 KCNMA1gene and characterized by their large conductance of potassium ions (K+) through cell membranes.[1]
BK channels are activated (opened) by changes in membrane electrical potential and/or by increases in concentration of intracellularcalcium ion (Ca2+).[2][3] 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 muscletone 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):
A unique transmembrane domain (S0)[5] that precedes the 6 transmembrane domains (S1-S6) conserved in all voltage-dependent K+ channels.
A voltage sensing domain (S1-S4).
A K+ 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.[3][6][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.[3][6][10][11]
Calcium-activated BK potassium channel alpha subunit
3U6N – Open structure of the BK channel gating ring[11]
3MT5 – Crystal structure of the human BK gating apparatus[3]
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[12] 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 monoxide[15][16] and hydrogen sulphide.[17]
↑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. PMID14675531.
↑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. PMID11301020.
↑Pico A. 2003. RCK domain model of calcium activation in BK channels. PhD thesis. The Rockfeller University, New York.
↑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. PMID15926865.
↑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. PMID11496927.
↑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. PMID15664403.
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Knaus HG, Folander K, Garcia-Calvo M, et al. (1994). "Primary sequence and immunological characterization of beta-subunit of high conductance Ca(2+)-activated K+ channel from smooth muscle". J. Biol. Chem. 269 (25): 17274–8. PMID8006036.
Meera P, Wallner M, Jiang Z, Toro L (1996). "A calcium switch for the functional coupling between alpha (hslo) and beta subunits (KV,Ca beta) of maxi K channels". FEBS Lett. 382 (1–2): 84–8. doi:10.1016/0014-5793(96)00151-2. PMID8612769.
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Díaz L, Meera P, Amigo J, et al. (1999). "Role of the S4 segment in a voltage-dependent calcium-sensitive potassium (hSlo) channel". J. Biol. Chem. 273 (49): 32430–6. doi:10.1074/jbc.273.49.32430. PMID9829973.
Valverde MA, Rojas P, Amigo J, et al. (1999). "Acute activation of Maxi-K channels (hSlo) by estradiol binding to the beta subunit". Science. 285 (5435): 1929–31. doi:10.1126/science.285.5435.1929. PMID10489376.
Brenner R, Jegla TJ, Wickenden A, et al. (2000). "Cloning and functional characterization of novel large conductance calcium-activated potassium channel beta subunits, hKCNMB3 and hKCNMB4". J. Biol. Chem. 275 (9): 6453–61. doi:10.1074/jbc.275.9.6453. PMID10692449.
Quirk JC, Reinhart PH (2001). "Identification of a novel tetramerization domain in large conductance K(ca) channels". Neuron. 32 (1): 13–23. doi:10.1016/S0896-6273(01)00444-5. PMID11604135.
Soto MA, González C, Lissi E, et al. (2002). "Ca(2+)-activated K+ channel inhibition by reactive oxygen species". Am. J. Physiol., Cell Physiol. 282 (3): C461–71. doi:10.1152/ajpcell.00167.2001. PMID11832330.
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