Regulation of RhoGEF proteins by G 12/13-coupled receptors

Abstract

G protein-coupled receptors (GPCRs) represent a large family of seven transmembrane receptors, which communicate extracellular signals into the cellular lumen. The human genome contains 720-800 GPCRs, and their diverse signal characteristics are determined by their specific tissue and subcellular expression profiles, as well as their coupling profile to the various G protein families (G s, G i, G q, G 12). The G protein coupling pattern links GPCR activation to the specific downstream effector pathways. G 12/13 signalling of GPCRs has been studied only recently in more detail, and involves activation of RhoGTPase nucleotide exchange factors (RhoGEFs). Four mammalian RhoGEFs regulated by G 12/13 proteins are known: p115-RhoGEF, PSD-95/Disc-large/ZO-1 homology-RhoGEF, leukemia-associated RhoGEF and lymphoid blast crisis-RhoGEF. These link GPCRs to activation of the small monomeric GTPase RhoA, and other downstream effectors. Misregulated G 12/13 signalling is involved in multiple pathophysiological conditions such as cancer, cardiovascular diseases, arterial and pulmonary hypertension, and bronchial asthma. Specific targeting of G 12/13 signalling-related diseases of GPCRs hence provides novel therapeutic approaches. Assays to quantitatively measure GPCR-mediated activation of G 12/13 are only emerging, and are required to understand the G 12/13-linked pharmacology. The review gives an overview of G 12/13 signalling of GPCRs with a focus on RhoGEF proteins as the immediate mediators of G 12/13 activation. © 2009 The British Pharmacological Society.