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Sci. STKE, 11 February 2003
Vol. 2003, Issue 169, p. tw61
[DOI: 10.1126/stke.2003.169.tw61]

EDITORS' CHOICE

G Proteins Setting Gβ{gamma} Free Without a Receptor

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 β{gamma} heterodimer (Gβ{gamma}), 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 Gβ{gamma}, it did not require GTP in the medium. High Na+ reduced the association of radiolabeled Gβ{gamma} with a GDP-bound fusion protein of Gα with glutathione S-transferase (GST-GαGDP) and decreased Gβ{gamma} binding to GST-GαGDP as assessed by surface plasmon resonance. Mild overexpression of Gα (which should increase the fraction of total Gβ{gamma} bound to GαGDP) enhanced slow Na+-dependent activation of GIRK. These data suggest that Na+ regulates the resting equilibrium between free Gβ{gamma} and Gβ{gamma} bound to GαGDP and may, under some conditions, act as a second messenger coupling electrical activity in excitable cells to GPCR-independent effects of Gβ{gamma} 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 Gβ{gamma}, activating G protein-gated K+ channels. J. Biol. Chem. 278, 3840-3845 (2003). [Abstract] [Full Text]

Citation: Setting Gβ{gamma} Free Without a Receptor. Sci. STKE 2003, tw61 (2003).



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