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BK channels (Big Potassium), also called Maxi-K or slo1, are potassium channels characterized by their large conductance for potassium ions (K+) through cell membranes. These channels are activated (opened) by changes in membrane electrical potential and/or by increases in concentration of intracellularcalcium 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 (an increase 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).[3]
BK channels are essential for the regulation of several key physiological processes including smooth muscletone and neuronal excitability.[4] 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 exogenous doses (> 100 mM) [5] that have been shown to correspond to biologically relevant internal ethanol concentrations.[6] It remains to be determined if BK channels contribute to intoxication in humans.
Structure
As with most other voltage-gated 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):
A unique transmembrane domain (S0)[7] 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 (Regulator of Conductance of K+) domains that assemble into an octameric gating ring on the intracellular side of the tetrameric channel.[8][9][10][11][12] The CTD contains four primary binding sites for Ca2+, called "calcium bowls", encoded within the second RCK domain of each monomer.[2][8][12][13]
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)[8]
3U6N - Open Structure of the BK channel Gating Ring[13]
Pharmacology
BK channels are pharmacological targets for the treatment of several medical disorders including stroke[14] and overactive bladder.[15] Although pharmaceutical companies have attempted to develop synthetic molecules targeting BK channels,[16] their efforts have proved largely ineffective. For instance, BMS-204352, a molecule developed by Bristol-Myers Squibb, failed to improve clinical outcome in stroke patients compared to placebo.[17] However, BKCa channels are reduced in patients suffering from the Fragile X syndrome[18] and the agonist, BMS-204352, corrects some of the deficits observed in Fmr1knockout mice, a model of Fragile X syndrome.[19]
BK channels have also been found to be activated by exogenous pollutants and endogenous gasotransmitters carbon monoxide[20][21] and hydrogen sulphide.[22]
^Davies AG, Pierce-Shimomura JT, Kim H, VanHoven MK, Thiele TR, Bonci A, Bargmann CI, McIntire SL (Dec 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 (Mar 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.
^Laumonnier F, Roger S, Guérin P, Molinari F, M'rad R, Cahard D, Belhadj A, Halayem M, Persico AM, Elia M, Romano V, Holbert S, Andres C, Chaabouni H, Colleaux L, Constant J, Le Guennec JY, Briault S (2006). "Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation". The American Journal of Psychiatry. 163 (9): 1622–1629. doi:10.1176/ajp.2006.163.9.1622. PMID16946189.
^Dubuis E, Potier M, Wang R, Vandier C (Feb 2005). "Continuous inhalation of carbon monoxide attenuates hypoxic pulmonary hypertension development presumably through activation of BKCa channels". Cardiovascular Research. 65 (3): 751–61. doi:10.1016/j.cardiores.2004.11.007. PMID15664403.
^McLeod JF, Leempoels JM, Peng SX, Dax SL, Myers LJ, Golder FJ (Nov 2014). "GAL-021, a new intravenous BKCa-channel blocker, is well tolerated and stimulates ventilation in healthy volunteers". Br J Anaesth. 113 (5): 875–83. doi:10.1093/bja/aeu182. PMID24989775.
^Golder, Francis J.; Dax, Scott; Baby, Santhosh M.; Gruber, Ryan; Hoshi, Toshinori; Ideo, Courtney; Kennedy, Andrew; Peng, Sean; Puskovic, Veljko; Ritchie, David; Woodward, Richard; Wardle, Robert L.; Van Scott, Michael R.; Mannion, James C.; MacIntyre, D. Euan (2015). "Identification and Characterization of GAL-021 as a Novel Breathing Control Modulator". Anesthesiology. 123 (5): 1093–1104. doi:10.1097/ALN.0000000000000844. ISSN0003-3022. PMID26352381.
