Nature 383, 172 - 175 (12 September 1996); doi:10.1038/383172a0

RGS family members: GTPase-activating proteins for heterotrimeric G-protein -subunits

Ned Watson^*, Maurine E. Linder^*, Kirk M. Druey^†, John H. Kehrl^† & Kendall J. Blumer^*

^*Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA
^†Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA

SIGNALLING pathways using heterotrimeric guanine-nucleotide-binding-proteins (G proteins) trigger physiological responses elicited by hormones, neurotransmitters and sensory stimuli^1,2. GTP binding activates G proteins by dissociating G from G subunits, and GTP hydrolysis by G subunits deactivates G proteins by allowing heterotrimers to reform. However, deactivation of G-protein signalling pathways in vivo can occur 10- to 100-fold faster than the rate of GTP hydrolysis of G subunits in vitro ^3–8, suggesting that GTPase-activating proteins (GAPs) deactivate G subunits. Here we report that RGS^9,10 (for regulator of G-protein signalling) proteins are GAPs for G subunits. RGS1, RGS4 and GAIP (for G-interacting protein¹⁷) bind specifically and tightly to G_I and G_o in cell membranes treated with GDP and AlF₄ ^-, and are GAPs for G_I G_o and transducin -subunits, but not for G_s. Thus, these RGS proteins are likely to regulate a subset of the G-protein signalling pathways in mammalian cells. Our results provide insight into the mechanisms that govern the duration and specificity of physiological responses elicited by G-protein-mediated signalling pathways.

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