1.A.2 Inward Rectifier K Channel (IRK-C) Family
IRK channels possess the ''minimal channel-forming structure'' with only a P domain, characteristic of the channel proteins of the VIC family (TC #1.A.1), and two flanking transmembrane spanners. They may exist in the membrane as homo- or heterooligomers. They have a greater tendency to let K flow into the cell than out. 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.
Mutations in SUR1 are the cause of familial persistent hyperinsulinemic hypoglycemia in infancy (PHHI), an autosomal recessive disorder characterized by unregulated insulin secretion in the pancreas. SUR1 has two nucleotide binding domains, NBD1 (binds ATP) and NBD2 (binds Mg-ADP). Both NBDs mediate nucleotide regulation of pore activity. Kir6.2, unlike many other Kir channels, cannot form plasma membrane functional channels when expressed without SUR1. This is due to a trafficking signal in SUR1 (Partridge et al., 2001).
The crystal structure (Kuo et al., 2003) and function (Enkvetchakul et al., 2004) of bacterial members of the IRK-C family have been determined. KirBac1.1, from Burkholderia pseudomallei, is 333 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 (Enkvetchakul et al., 2004).
Kir3 channels control heart rate and neuronal excitability through GTP-binding (G) proteins and phosphoinositide signaling pathways. These channels were the first characterized effectors of the betagamma subunits of G proteins. The crystal structure of a chimera between the cytosolic domain
of a mammalian Kir3.1 and the transmembrane region of a prokaryotic KirBac1.3 (Kir3.1 chimera) provided invaluable structural insight. This channel has been functionally reconstituted in planar lipid bilayers (Leal-Pinto et al. 2010). The chimera behaved like a Kir channel, displaying a
requirement for PIP(2) and Mg2+-dependent inward rectification. The channel was blocked by external tertiapin Q. The three-dimensional reconstruction of the chimera by single particle electron microscopy revealed a structure consistent with the crystal structure. Channel activity could be stimulated by ethanol and activated G proteins but the presence of both activated G-alpha and G-betagamma subunits was required for gating.
The generalized transport reaction catalyzed by IRK-C family proteins is:
K+ (out) K+ (in).