Structural Basis of Dopamine Receptor Activation

Abstract

G protein-coupled receptors (GPCRs) are seven transmembrane (TM) proteins representing the largest and most universally expressed cell surface recep- tors and are present in almost all species and in a wide variety of cells. Here we will focus our attention on the catecholamine-binding GPCRs and in particular on the dopamine receptors. The catecholamine-binding GPCRs form a group of rhodopsin-like GPCRs composed of adrenoceptors, which are endogenously acti- vated by epinephrine and norepinephrine, and dopamine receptors. We review the different “molecular switches” involved in GPCR activation and we emphasize the importance of extracellular loop 2 (ECL2) in ligand binding. A better understand- ing of the functional role of ECL2 can be achieved after the release of the crystal structures of B2AR and rhodopsin, which are consistent with dopamine D2 receptor substituted cysteine accessibility method (SCAM) experimental data. Even though reconstituted GPCR monomers appear sufficient to activate a G protein, in the native setting their dimerization/oligomerization may modulate activation through changes at the dimerization interface or a larger-scale reorientation of the pro- tomers. Therefore, the structural aspects of oligomerization and their importance for receptor activation and signaling are also addressed.