Inward-rectifier potassium channel
Inward-rectifier potassium channels (Kir, IRK) are a specific lipid-gated subset of potassium channels. To date, seven subfamilies have been identified in various mammalian cell types,[1] plants,[2] and bacteria.[3] They are activated by phosphatidylinositol 4,5-bisphosphate (PIP2). The malfunction of the channels has been implicated in several diseases.[4][5] IRK channels possess a pore domain, homologous to that of voltage-gated ion channels, and flanking transmembrane segments (TMSs). They may exist in the membrane as homo- or heterooligomers and each monomer possesses between 2 and 4 TMSs. In terms of function, these proteins transport potassium (K+), with a greater tendency for K+ uptake than K+ export.[3] The process of inward-rectification was discovered by Denis Noble in cardiac muscle cells in 1960s[6] and by Richard Adrian and Alan Hodgkin in 1970 in skeletal muscle cells.[7]
Mechanism of inward rectification[edit]
The phenomenon of inward rectification of Kir channels is the result of high-affinity block by endogenous polyamines, namely spermine, as well as magnesium ions, that plug the channel pore at positive potentials, resulting in a decrease in outward currents. This voltage-dependent block by polyamines results in efficient conduction of current only in the inward direction. While the principal idea of polyamine block is understood, the specific mechanisms are still controversial.[11]
Activation by PIP2[edit]
All Kir channels require phosphatidylinositol 4,5-bisphosphate (PIP2) for activation.[12] PIP2 binds to and directly activates Kir 2.2 with agonist-like properties.[13] In this regard Kir channels are PIP2 ligand-gated ion channels.
Regulation[edit]
Voltage-dependence may be regulated by external K+, by internal Mg2+, by internal ATP and/or by G-proteins. The P domains of IRK channels exhibit limited sequence similarity to those of the VIC family. Inward rectifiers play a role in setting cellular membrane potentials, and closing of these channels upon depolarization permits the occurrence of long duration action potentials with a plateau phase. Inward rectifiers lack the intrinsic voltage sensing helices found in many VIC family channels. In a few cases, those of Kir1.1a, Kir6.1 and Kir6.2, for example, direct interaction with a member of the ABC superfamily has been proposed to confer unique functional and regulatory properties to the heteromeric complex, including sensitivity to ATP. These ATP-sensitive channels are found in many body tissues. They render channel activity responsive to the cytoplasmic ATP/ADP ratio (increased ATP/ADP closes the channel). The human SUR1 and SUR2 sulfonylurea receptors (spQ09428 and Q15527, respectively) are the ABC proteins that regulate both the Kir6.1 and Kir6.2 channels in response to ATP, and CFTR (TC #3.A.1.208.4) may regulate Kir1.1a.[16]
Structure[edit]
The crystal structure[17] and function[18] of bacterial members of the IRK-C family have been determined. KirBac1.1, from Burkholderia pseudomallei, is 333 amino acyl residues (aas) long with two N-terminal TMSs flanking a P-loop (residues 1-150), and the C-terminal half of the protein is hydrophilic. It transports monovalent cations with the selectivity: K ≈ Rb ≈ Cs ≫ Li ≈ Na ≈ NMGM (protonated N-methyl-D-glucamine). Activity is inhibited by Ba2+, Ca2+, and low pH.[18]