Crystal Structure of the Mammalian GIRK2 K+ Channel and Gating Regulation by G Proteins, PIP2, and Sodium

Abstract

Summary G-protein-gated K+ channels (Kir3.1–Kir3.4) control electrical excitability in many different cells. Among their functions relevant to human physiology and disease, they regulate the heart rate and govern a wide range of neuronal activities. Here we present the first crystal structures of a G-protein-gated K+ channel. By comparing the wild-type structure to that of a constitutively active mutant, we identify a global conformational change through which G-proteins could open a G-loop gate in the cytoplasmic domain. The structures of both channels in the absence and presence of PIP2 show that G-proteins open only the G-loop gate in the absence of PIP2, but in the presence of PIP2 the G-loop gate and a second inner helix gate become coupled, so that both gates open. We also identify a strategically located Na+ ion-binding site, which would allow intracellular Na+ to modulate GIRK channel activity. These data provide a mechanistic description of multi-ligand regulation of GIRK channel gating.

Characterization of Rebound Depolarization in Neurons of the Rat Medial Geniculate Body In Vitro

“…and Mg 2? directly influence the activation of GIRK channels [56][57][58]. Neurotransmitters, such as acetylcholine and 5-hydroxytryptamine, may modulate RD by activating GIRK channels [59,60].…”

Analysis of the selectivity filter of the voltage-gated sodium channel NavRh

“…The pore of KcsA only permits the passage of dehydrated potassium ions [10,11]. This property is highly conserved in most types of potassium channels [4][5][6][12][13][14][15][16][17]. The ion permeation, however, is different in Na v channels where Na + is…”

Potassium channels in the sinoatrial node and their role in heart rate control

“…The domains on the Kir3.0 subunits that bind the G βγ subunits and also the key residues on G βγ have been mapped [36,37]. There are crystal structures of the channel complex with and without G βγ subunits bound [38]. Anionic phospholipids particularly phosphatidylinositol- [4,5]-bisphosphate and sodium are known to be key modulators of the gating and a number of site-directed mutagenesis studies together with structural work have suggested models predicting how this might occur [38–40].…”

“…There are crystal structures of the channel complex with and without G βγ subunits bound [38]. Anionic phospholipids particularly phosphatidylinositol- [4,5]-bisphosphate and sodium are known to be key modulators of the gating and a number of site-directed mutagenesis studies together with structural work have suggested models predicting how this might occur [38–40]. However the inhibitory G-protein α subunit also participates in determining the selectivity of activation but not directly in activation itself [41].…”