The Role of Oligomerization in G Protein-Coupled Receptor Maturation

A large body of evidence now shows that the basic functional unit of seven transmembrane-spanning G protein-coupled receptors (GPCRs) is a dimer, with the possibility of the existence of higher order oligomeric species. GPCR oligomerization has been demonstrated to be a physiological process that defines receptor pharmacology and function ( 1 , 2 ). There is substantial evidence indicating that these receptors are assembled as dimers and, possibly, oligomers prior to cell-surface expression ( Fig. 1 ). Although it has generally been accepted that constitutive GPCR oligomers exist at the plasma membrane, there is evidence demonstrating that the extent of oligomerization at the plasma membrane may be altered by ligand induction ( 3 – 5 ) ( Fig. 1 ). For many other classes of cell-surface receptors, oligomerization has been found to be a prerequisite for activation and signaling. For example, the epidermal growth factor receptor, a prototypical member of the tyrosine kinase (TK) family, requires a ligand-induced dimeric configuration for the auto-phosphorylation of tyrosine residues on the cytoplasmic domain and subsequent recruitment of various signaling proteins ( 6 ). With the exception of the insulin receptor, agonist-induced dimerization appears to be the rule of thumb for TKs. Conversely, a large proportion of receptors belonging to the cytokine receptor superfamily have been reported as intracellularly derived dimers at the plasma membrane ( 7 – 10 ). Ligand binding triggers a conformational change in these receptors, facilitating Janus kinase-mediated phosphorylation of various cytosolic substrates ( 11 ). Although there is a wealth of knowledge regarding the formation and functional significance of oligomerization in these other receptor families, progress is still being made to determine the cellular implications of the relatively novel concept of GPCR oligomerization. Maturation process of a GPCR oligomer. GPCR monomers are synthesized in the endoplasmic reticulum (ER) and inserted in the membrane sequentially as transmembrane domain pairs ( 1 ). Folding of the polypeptide is mediated by specific ER-resident molecular chaperones, which may also function to mediate dimeric assembly ( 2 , 3 ). Higher order oligomeric assembly may occur with other dimers in the ER (4A) and these complexes will then be trafficked to the cell surface as constitutively formed GPCR oligomers (5A). Alternatively, ER-formed dimers may traffic to the plasma membrane (4B, 5B) and form higher order oligomeric units upon agonist induction. These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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