Allosterism within GPCR oligomers: Back to symmetry

Abstract

The Monod-Wyman-Changeux (MWC) model provided the most influential interpretation of allosterism within the frame of a symmetric oligomeric structure of regulatory enzymes. The initial studies of allosteric properties of G protein-coupled receptors (GPCRs) departed from these classical concepts of allosterism, considering GPCR monomers as main functional units. However, the phenomenon of GPCR homo- and heteromerization is becoming widely accepted. A new concept is that the pentameric structure constituted by one GPCR homodimer and one heterotrimeric G protein provides a main functional symmetric unit and oligomeric entities can be viewed as multiples of dimers. GPCR heteromerization opens up the possibility of allosteric interactions between different orthosteric ligands. Furthermore, the same properties of allosteric ligands demonstrated when considering GPCR as putative monomeric entities, mainly saturability, ability to separately alter the affinity and efficacy of the orthosteric ligand, probe dependence and functional selectivity, are also demonstrable with interactions between orthosteric ligands within the GPCR heteromer. A GPCR heterotetramer constituted by two molecularly different homodimers coupled to their cognate G protein and to adenylyl cyclase seems to constitute a common structure of a GPCR heteromer. Recent studies indicate that the canonical Gs-Gi interaction at the adenylyl cyclase level is a specific property of the GPCR heterotetramer. The evidence for GPCR oligomerization and the elucidation of symmetrical minimal functional units of GPCR homomers and heteromers, brings back the classical concepts of allosterism and promotes oligomerization and allosterism within GPCR oligomers as necessary elements in the research of GPCR physiology and pharmacology.