G_12/13-dependent signaling of G-protein-coupled receptors: disease context and impact on drug discovery

ISSN： 1746-0441

Source： Expert Opinion on Drug Discovery, Vol.2, Iss.12, 2007-12, pp. : 1591-1604

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Abstract

G-protein-coupled receptors (GPCRs) transmit extracellular signals across the plasma membrane via intracellular activation of heterotrimeric G proteins. The signal transduction pathways of G_s, G_i and G_q protein families are widely studied, whereas signaling properties of G₁₂ proteins are only emerging. Many GPCRs were found to couple to G_12/13 proteins in addition to coupling to one or more other types of G proteins. G_12/13 proteins couple GPCRs to activation of the small monomeric GTPase RhoA. Activation of RhoA modulates various downstream effector systems relevant to diseases such as hypertension, artherosclerosis, asthma and cancer. GPCR screening assays exist for G_s-, G_i- and G_q-linked pathways, whereas a drug-screening assay for the G₁₂-Rho pathway was developed only recently. The review gives an overview of the present understanding of the G_12/13-related biology of GPCRs.