Sci. STKE, 11 February 2003
G Proteins Setting Gβ 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 heterodimer (Gβ), 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, it did not require GTP in the medium. High Na+ reduced the association of radiolabeled Gβ with a GDP-bound fusion protein of Gα with glutathione S-transferase (GST-GαGDP) and decreased Gβ binding to GST-GαGDP as assessed by surface plasmon resonance. Mild overexpression of Gα (which should increase the fraction of total Gβ bound to GαGDP) enhanced slow Na+-dependent activation of GIRK. These data suggest that Na+ regulates the resting equilibrium between free Gβ and Gβ 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 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, activating G protein-gated K+ channels. J. Biol. Chem. 278, 3840-3845 (2003). [Abstract] [Full Text]
Citation: Setting Gβ Free Without a Receptor. Sci. STKE 2003, tw61 (2003).
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