Editors' ChoiceG Proteins

Setting Gβγ Free Without a Receptor

Science's STKE  11 Feb 2003:
Vol. 2003, Issue 169, pp. tw61-TW61
DOI: 10.1126/stke.2003.169.tw61

Rishal et al. have described a novel mode of heterotrimeric guanine nucleotide-binding protein (G protein) regulation that points to a possible role for Na+ as a second messenger. G protein-activated inward rectifier K+ channels (GIRKs) play a role in regulating the heartbeat and mediate the effects of many inhibitory neurotransmitters. These channels are activated by the G protein βγ heterodimer (Gβγ), which is released from the heterotrimer after stimulation of G protein-coupled receptors (GPCRs) and GTP binding to the Gα subunit. GIRKs are also rapidly activated by intracellular Na+ independently of G proteins. Rishal et al. used inside-out patch clamp analysis to investigate activation of GIRK channels expressed in Xenopus oocytes. They observed a slow phase of Na+-dependent activation in both wild-type channels and mutant channels lacking fast Na+-dependent activation. Although slow Na+ activation of GIRK was inhibited by a protein that bound Gβγ, it did not require GTP in the medium. High Na+ reduced the association of radiolabeled Gβγ with a GDP-bound fusion protein of Gα with glutathione S-transferase (GST-GαGDP) and decreased Gβγ binding to GST-GαGDP as assessed by surface plasmon resonance. Mild overexpression of Gα (which should increase the fraction of total Gβγ bound to GαGDP) enhanced slow Na+-dependent activation of GIRK. These data suggest that Na+ regulates the resting equilibrium between free Gβγ and Gβγ bound to GαGDP and may, under some conditions, act as a second messenger coupling electrical activity in excitable cells to GPCR-independent effects of Gβγ on target proteins.

I. Rishal, T. Keren-Raifman, D. Yakubovich, T. Ivanina, C. W. Dessauer, V. Z. Slepak, N. Dascal, Na+ promotes the dissociation between GαGDP and Gβγ, activating G protein-gated K+ channels. J. Biol. Chem. 278, 3840-3845 (2003). [Abstract] [Full Text]