TCDB is operated by the Saier Lab Bioinformatics Group

1.A.2 The Inward Rectifier K+ Channel (IRK-C) Family

IRK or GIRK 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.  There are 15 Kir (inward rectifying) channels in humans, and most are in TCDB.  Most of them are found in TCDB  in family 1.A.2.

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). Epsilon toxin from Clostridium perfringens causes inhibition of potassium inward rectifier (Kir) channels, possibly by an indirect mechanism, in oligodendrocytes (Bossu et al. 2020).

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 (Doupnik 2008). 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 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.

GIRK (Kir3) channels are members of the large family of inwardly rectifying potassium channels (Kir1-Kir7). GIRK channels, like all other Kir channels, possess an extrinsic mechanism of inward rectification involving intracellular Mg2+ and polyamines that occlude the conduction pathway at membrane potentials positive to EK. More than 20 high-resolution atomic structures containing GIRK channel cytoplasmic domains and transmembrane domains have been solved. These structures have provided valuable insight into the structural determinants of many of the properties common to all inward rectifiers, such as permeation and rectification, as well as revealing the structural bases for GIRK channel gating (Glaaser and Slesinger 2015).

GIRK channels are abundantly expressed in the heart and require that phosphatidylinositol bisphosphate (PIP2) is present so that intracellular channel-gating regulators such as Gbetagamma (Gβγ)and Na+ ions maintain the channel-open state. Li et al. 2019 determined how each regulator uses the channel domain movements to control gate transitions. Na+ controls the cytosolic gate of the channel through an anti-clockwise rotation, whereas Gbetagamma stabilizes the transmembrane gate in the open state through a rocking movement of the cytosolic domain. Both effects altered the way by which the channel interacts with PIP2 and thereby stabilized the open states of the respective gates (Li et al. 2019). 

Inwardly rectifying potassium (Kir) channels play a key role in maintaining the resting membrane potential and supporting potassium homeostasis. There are many variants of Kir channels, which are usually tetramers in which the main subunit has two trans-membrane helices attached to two N- and C-terminal cytoplasmic tails with a pore-forming loop in between that contains the selectivity filter. These channels have domains that are strongly modulated by molecules present in nutrients found in different diets, such as phosphoinositols, polyamines and Mg2+ (Ferreira et al. 2023).

The generalized transport reaction catalyzed by IRK-C family proteins is:

K+ (out) K+ (in)

This family belongs to the: VIC Superfamily.

References associated with 1.A.2 family:

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