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

Abstract

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 Gα from Gβγ subunits, and GTP hydrolysis by Gα 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 Gα subunits in vitro^3–8, suggesting that GTPase-activating proteins (GAPs) deactivate Gα subunits. Here we report that RGS^9,10 (for regulator of G-protein signalling) proteins are GAPs for Gα subunits. RGS1, RGS4 and GAIP (for Gα-interacting protein¹⁷) bind specifically and tightly to Gα_I and Gα_o in cell membranes treated with GDP and AlF₄⁻, and are GAPs for Gα_I Gα_o and transducin α-subunits, but not for Gα_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.