Calcium-activated potassium channel subunit alpha-1

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 is_associated_with::potassium channel encoded by the KCNMA1 is_associated_with::gene and characterized by their large conductance of is_associated_with::potassium ions (K+) through is_associated_with::cell membranes.

Function
BK channels are activated (opened) by changes in membrane electrical potential and/or by increases in concentration of is_associated_with::intracellular is_associated_with::calcium ion (Ca2+). Opening of BK channels allows K+ to passively flow through the channel, down the is_associated_with::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 is_associated_with::electrical potential across the cell membrane) and a decrease in cell excitability (a decrease in the probability that the cell will transmit an is_associated_with::action potential).

BK channels are essential for the regulation of several key physiological processes including is_associated_with::smooth muscle tone and neuronal excitability. They control the contraction of smooth muscle and are involved with the is_associated_with::electrical tuning of is_associated_with::hair cells in the is_associated_with::cochlea. BK channels also contribute to the behavioral effects of is_associated_with::ethanol in the worm C. elegans under high concentrations (> 100 mM, or approximately 0.50% BAC). 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 is_associated_with::KCNMB1, is_associated_with::KCNMB2, is_associated_with::KCNMB3, or is_associated_with::KCNMB4) can associate with the tetrametic channel. Alternatively spliced transcript variants encoding different isoforms have been identified.

Each BK channel alpha subunit consists of (from N- to C-terminal):
 * 1) A unique is_associated_with::transmembrane domain (S0) 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.    The CTD contains four primary binding sites for Ca2+, called "calcium bowls", encoded within the second RCK domain of each monomer.

Available X-ray structures include:
 * – Open structure of the BK channel gating ring
 * – Crystal structure of the human BK gating apparatus
 * – Structure of the intracellular gating ring from the human high-conductance Ca2+ gated K+ channel (BK Channel)

Pharmacology
BK channels are pharmacological targets for the treatment of stroke. Various pharmaceutical companies developed synthetic molecules activating these channels in order to prevent excessive is_associated_with::neurotoxic calcium entry in neurons. But BMS-204352 (MaxiPost) a molecule developed by is_associated_with::Bristol-Myers Squibb failed to improve clinical outcome in stroke patients compared to is_associated_with::placebo. BK channels have also been found to be activated by exogenous pollutants and endogenous gazotransmitters carbon monoxide and hydrogen sulphide.

BK channels are blocked by tetraethylammonium (TEA), is_associated_with::paxilline and is_associated_with::iberiotoxin.