Functional Role(s) of Dimeric Complexes Formed from G-Protein-Coupled Receptors

Findings from emerging studies with a variety of G-protein-coupled receptors (GPCRs) indicate that GPCR hetero-oligomerization alters receptor function by forming new signaling units with distinct properties, which are involved in specific pathophysiological mechanisms. This chapter reviews the evidence for receptor dimerization/oligomerization and describes how this leads to the modulation of the properties of individual receptors. It begins with presenting a historical perspective of GPCR dimerization, presenting the indirect evidence, functional complementation analysis, biochemical and biophysical evidence, and physical evidence to demonstrate direct association of proteins to form functional receptors. Following this, it reviews the studies that have examined the effect of association between two distinct receptors on their function. These studies are of scientific interest since they examine the influence of heterodimerization on receptor function at the molecular level. Also, they provide ample proof that GPCR heterodimerization allows for a new level of complexity in the regulation of the properties and thus functions of GPCRs. Furthermore, this study indicates that heterodimerization leads to the formation of new complexes with altered function in specific tissues, and especially in pathological contexts. This is explained using the examples of AT1R–B2Rin pregnancy-induced pre-eclampsia, β2AR–AT1R and β2AR–β1 ARin cardiomyocytes, β2AR-prostaglandin receptor (EP1R) in asthma, 5HT2AR–mGluR2 in schizophrenia, and DOR–KORin spinal analgesia. These examples suggest that GPCR heterodimers represent new drug targets, with high tissue specificity, especially in pathophysiological contexts.