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BK channel From Wikipedia, the free encyclopedia 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 intracellular calcium 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 muscle tone 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
Structurally, BK channels are homologous to voltage- and ligand-gated K+ channels, having a voltage sensor and pore as the membrane-spanning domain and a cytosolic domain for the binding of intracellular Ca2+ and Mg2+. [7] Each monomer of the channel-forming alpha subunit is the product of the KCNMA1 gene (also known as Slo1). The Slo1 subunit has three main structural domains, each with a distinct function: the voltage sensing domain (VSD) senses membrane potential across the membrane, the cytosolic domain (senses calcium concentration, Ca2+ ions), and the pore-gate domain (PGD) which opens and closes to regulate potassium permeation. The activation gate resides in the PGD, which is located at either the cytosolic side of S6 or the selectivity filter (selectivity is the preference of a channel to conduct a specific ion). [7] The Voltage sensing domain and pore-gated domain are called the membrane-spanning domains and are formed by transmembrane segments S1-S4 and S5-S6, respectively. Within the S4 helix contains a series of positively charged residues which serve as the primary voltage sensor [13]. BK channels are quite similar to voltage gated K+ channels, however, in BK channels only one positively charged residue (Arg213) is involved in voltage sensing across the membrane. [7] Also unique to BK channels is an additional S0 segment, this segment is required for β subunit modulation [14,15] and voltage sensitivity. [16] The Cytosolic domain is composed of two RCK (regulator of K+ conductance) domains, RCK1 and RCK2. These domains contain two high affinity Ca2+ binding sites: one in the RCK1 domain and the other in a region termed the Ca2+ bowl that consists of a series of Aspartic acid (Asp) residues that are located in the RCK2 domain. The Mg2+ binding site is located between the VSD and the cytosolic domain, formed by Asp residues within the S0-S1 loop, Asparagine residues in the cytosolic end of S2, and Glutamine residues in RCK1. [7] In forming the Mg2+ binding site, two residues come from the RCK1 of one Slo1 subunit and the other two residues come from the VSD of the neighboring subunit. In order for these residues to coordinate the Mg2+ ion, the VSD and cytosolic domain from neighboring subunits must be in close proximity. [7] Modulatory beta subunits (encoded by KCNMB1, KCNMB2, KCNMB3, or KCNMB4) can associate with the tetrametic channel. There are four types of β subunits (β1-4), each of which have different expression patterns that modify the gating properties of the BK channel. The β1 subunit is primarily responsible for smooth muscle cell expression, both β2 and β3 subunits are neuronally expressed, while β4 is expressed within the brain. [7]  	The VSD associates with the PGD via three major interactions: Physical connection between the VSD and PGD through the S4-S5 linker. Interactions between the S4-S5 linker and the cytosolic side of S6. Interactions between S4 and S5 of a neighboring subunit.

BK channel Regulation
BK channels can be regulated by: -Membrane voltage -A weaker voltage sensitivity allows BK channels to function in a wide range of membrane potentials, so that it can properly perform its physiological function -Intracellular chemical ligands (i.e. Ca2+) -Protein Kinases -Inhibition of BK channel activity by phosphorylation of S695 by protein kinase C (PKC) -This is dependent on the phosphorylation of S1151 in C terminus of channel alpha-subunit -Only one of these phosphorylations in the tetrameric structure needs to occur for inhibition to be successful -Protein phosphatase 1 counteracts phosphorylation of S695 -PKC decreases channel opening probability by shortening the channel open time and prolonging the closed state of the channel -PKC did NOT affect the single-channel conductance, voltage dependence, or the calcium sensitivity of BK channels -Inhibition of BK channels by PKC depends on the unconditional and conditional phosphorylation of the C-terminal serine residues 1151 and 695, respectively. The inhibition of BK channel conductance by PKC is due to a decrease of channel open probability without changing the unitary current amplitude. The voltage dependence and the Ca2+sensitivity of the BK channel are not affected by PKC. The phosphorylation of the BK channel by PKC abolishes the stimulatory effects of PKA and PKG http://www.pnas.org/content/107/17/8005 -Cytosolic Tail Domain (chemical sensor) -Multiple binding sites for ligands (i.e. protons, heme, phosphatidylinositol, PIP2, and ethanol) -Protons -Protonate the side chains of H365 and H394 -Carbon monoxide stimulates BK channels the same way -Ethanol -Activate BK channels in isolated inside-out membrane patches in the presence of Ca2+ -Heme -Inhibits BK channel activity by binding to the CTD with high affinity -PIP2 -PIP2 might tightly bind to BK channels and/or the intimate interactions between the CTD and the membrane spanning domain of BK channels create a physical barrier to limit the free diffusion of this highly charged lipid species -Activates channel when bound with intracellular Mg2+ to allow for interaction with the voltage sensor domain (VSD) -Mg2+ sensor… -Mg2+ can activate BK channels by shifting activation voltage to a more negative range -Independent from the high affinity Ca2+ dependent activation -E374 and E399 are critical to Mg2+ sensing -Two acidic residues in RCK1 domain -Mg2+ activates the channel only when the VSD stays in the activated state -Primarily responds to calcium (100 nM to 300 μM) -Increases channel opening when bound -Ca2+ bowl site vs. high affinity Ca2+ binding site -Not identical in terms of ion binding and allosteric activation mechanism -Voltage dependence was only seen with the binding of Ca2+ to RCK1 site but not the “bowl” -Ca2+ affinity is higher in the bowl at -80 mV than the binding site one -The Ca2+ bowl accelerates activation kinetics at low Ca2+ concentrations while RCK1 site influences both activation and deactivation kinetics -Structure(* own subheading) -Two regulators of K+ conductance (RCK) domains, connected by a ~100 amino acid linker protein -tetramer of four pore-forming ɑ subunits (these subunits are both alone and with β1-4 subunits) which play modulatory roles (11) -extra S0 transmembrane domain at the N-terminus and a intracellular tail at the C-terminus (11) (here we should insert a picture or link to another wiki page that shows structures) -S0 segment contributes to regulation of voltage-sensing domain (11) -long tail at C-terminus forms a gating ring that is triggered by molecules such as calcium, magnesium, and other lipid molecules (11)

BK Channel Activation/Inhibition
ɑ-KTx peptides have been shown to block potassium channels (11).

BK channels Mechanism
The β1 subunit of the BK channel is important for regulating intracellular calcium sensitivity (11). They act as a link between these intracellular calcium signals and extracellular stimuli (11).

BK channels effect on neuron, organ, body as whole
BK channels help regulate both the firing of neurons and neurotransmitter release (11). They not only play a role in the CNS (central nervous system -insert link here in wiki-) but also in smooth muscle contractions, the secretion of endocrine cells, and the proliferation of cells (11).

Pharmacology
A malfunction of BK channels can proliferate in many disorders such as: epilepsy, cancer, diabetes, asthma, and hypertension (11). Specifically, β1 defect can increase blood pressure and hydrosaline retention in the kidney (11). There have been research displaying that a blockage of BK channels results in an increase in neurotransmitter release, effectively indicating future therapeutic possibilities in cognition enhancement, improved memory, and relieving depression (11). Furthermore, increases in BK channel activation, through gain-of-function mutants and amplification, has links to epilepsy and cancer (11). A behavioral response to alcohol is also modulated by BK channels (5).