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

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Na⁺ Promotes the Dissociation between G_GDP and G, Activating G Protein-gated K⁺ Channels

Ida Rishal, Tal Keren-Raifman, Daniel Yakubovich, Tatiana Ivanina, Carmen W. Dessauer, Vladlen Z. Slepak, and Nathan Dascal (31 January 2003)
J. Biol. Chem. 278 (6), 3840. [DOI: 10.1074/jbc.C200605200]
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