Of GIRK channels, vitamin E transfer, and a vertebrate fluorescent protein

This month's installment of Generally Physiological concerns G protein–gated inward rectifier K + (GIRK) channel activation and role in the regulation of heart rate, intermembrane transfer of vitamin E, and identification of a ligand-inducible vertebrate fluorescent protein. A new twist in GIRK activation Neurotransmitters that signal through G protein–coupled receptors (GPCRs) can activate GIRK channels, eliciting K + efflux and consequently decreasing the excitability of the target cell. Ligand occupation of the GPCR promotes dissociation of the G protein into its G and G subunits; G is thereby freed to bind to and activate GIRK channels or other effectors (see Reuveny, 2013). However, the molecular details of GIRK channel activation have been unclear. Whorton and MacKinnon (2013) obtained the 3.5-Å resolution crystal structure of a homomeric GIRK channel (residues 52–380 of mouse GIRK2 [Kir3.2, found in neurons]) in a complex with G. They determined that the GIRK channel–G complex consisted of a GIRK2 tetramer, with one G dimer, as well as one molecule of the membrane phospholipid PI(4,5)P 2 (phosphatidyl-inositol-4,5-bisphosphate) and one Na + (both of which play a role in GIRK activation) bound per GIRK monomer (for a total of four G dimers, four PI(4,5) P 2 molecules, and four Na + ions per complex). A comparison of the structures of a GIRK channel bound to PIP 2 , but not G, the GIRK chan-nel–G complex, and a constitu-tively open GIRK mutant indicated that G, which bound at the interface between GIRK subunits, induced an 4° rotation of the cytoplasmic domains relative to the transmem-brane domains along with a partial opening of the channel's inner heli-cal gate. The authors thus propose that, consistent with the characteristic bursting kinetics observed with activation of single GIRK channels, G binding induces a " pre-open " conformation—intermediate between those of the closed and open chan-nels—from which the channel can rapidly fluctuate into the fully open and conducting conformation. GIRK channels have long been known to contribute to parasympathetic re-gu lation of cardiac function, in which acetylcholine released from the vagus binds to muscarinic receptors to activate cardiac G protein–activated, inwardly rectifying K + current (I KACh) in the sino-atrial node (SAN; the dominant cardiac pacemaker region) and reduce the heart rate. However, muscarinic signaling influences multiple ion channels implicated in cardiac function, and the precise role of I KACh remains incompletely understood.