Regulators of G-protein signalling: a novel protein family involved in timely deactivation and desensitization of signalling via heterotrimeric G proteins

In a variety of signalling pathways heterotrimeric guanine-nucleotide-bindi ng proteins (G proteins) trigger physiological responses elicited by hormon es, neurotransmitters and sensory stimuli. Receptor-induced GDP/ GTP exchan ge activates G proteins by dissociating G-protein alpha-subunits from the b eta gamma-dimers. Both alpha-subunits and beta gamma-dimers are involved in effector regulation. The deactivation of these active forms is controlled by the hydrolysis of GTP bound to alpha-subunits, allowing the inactive het erotrimer to reform. Termination of G-protein-mediated signalling in vivo i s 10- to 100-fold faster than the in vitro rate of GTP hydrolysis by alpha- subunits, suggesting that in analogy to the GTPases of the Ras-superfamily, GTPase-activating proteins (GAPs) are required to achieve timely deactivat ion. Recently, members of a novel protein superfamily, known as "regulators of G-protein signalling" (RGS), were identified as potent GAPs for at leas t one subset of heterotrimeric G-protein alpha-subunits. In this review, we intend to discuss the proposed mechanism by which RGS proteins exert GAP a ctivity for G-protein alpha-subunits as well as their specificities. The ro le of RGS proteins in desensitization and temporal resolution in certain si gnalling pathways will also be addressed.