BK channel

thumb|left|alt=BK Channel Diagram|BK Channel Structure

BK channels (big potassium), are large conductance calcium-activated potassium channels, and is also known as BKCa, Maxi-K, slo1, or Kca1.1. BK channels are voltage-gated potassium channels that conduct large amounts of potassium ions (K⁺) across the cell membrane, hence their name, big potassium. These channels can be activated (opened) by either electrical means, or by increasing Ca²⁺ concentrations in the cell. BK channels help regulate physiological processes, such as circadian behavioral rhythms and neuronal excitability. BK channels are also involved in many processes in the body, as it is a ubiquitous channel. They have a tetrameric structure that is composed of a transmembrane domain, voltage sensing domain, potassium channel domain, and a cytoplasmic C-terminal domain, with many X-ray structures for reference. Their function is to repolarize the membrane potential by allowing for potassium to flow outward, in response to a depolarization or increase in calcium levels.

Structure

Structurally, BK channels are homologous to voltage- and ligand-gated potassium channels, having a voltage sensor and pore as the membrane-spanning domain and a cytosolic domain for the binding of intracellular calcium and magnesium. The voltage sensing domain and pore-gated domain are collectively referred to as 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.

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. and voltage sensitivity.

The Cytosolic domain is composed of two RCK (regulator of potassium conductance) domains, RCK1 and RCK2. These domains contain two high affinity binding sites:

• One in the RCK1 domain.
• One in a region termed the bowl that consists of a series of Aspartic acid (Asp) residues that are located in the RCK2 domain.

The binding site is located between the VSD and the cytosolic domain, which is formed by: Asp residues within the S0-S1 loop, Asparagine residues in the cytosolic end of S2, and Glutamine residues in RCK1.

Inhibition of BK channel activity by phosphorylation of S695 by protein kinase C (PKC) 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 does not affect the single-channel conductance, voltage dependence, or the calcium sensitivity of BK channels. Voltage and calcium activate BK channels using two parallel mechanisms, with the voltage sensors and the bindings sites coupling to the activation gate independently, except for a weak interaction between the two mechanisms. The bowl accelerates activation kinetics at low concentrations while RCK1 site influences both activation and deactivation kinetics. This modulation of synaptic transmission and electrical discharge at the cellular level is due to BK channel expression in conjunction with other potassium-calcium channels. The opening of these channels causes a drive towards the potassium equilibrium potential and thus play a role in speeding up the repolarization of action potentials. The role that BK channels have in the fast phase of AHP has been studied extensively in the hippocampus. There are many BK channels in Purkinje cells in the cerebellum, thus highlighting their role in motor coordination and function. nitric oxide, and hydrogen sulphide. Mutations in the proteins involved with BK channels or genes encoding BK channels are involved in many diseases. A malfunction of BK channels can proliferate in many disorders such as: epilepsy, cancer, diabetes, asthma, and hypertension. and overactive bladder. There have been attempts to develop synthetic molecules targeting BK channels, however their efforts have proven largely ineffective thus far. For instance, BMS-204352, a molecule developed by Bristol Myers Squibb, failed to improve clinical outcome in stroke patients compared to placebo. However, there have been some success from the agonist to BKCa channels, BMS-204352, in treating deficits observed in Fmr1 knockout mice, a model of Fragile X syndrome. BK channels also function as a blocker in ischemia and are a focus in investigating its use as a therapy for stroke.