Constitutive activities and inverse agonism in dopamine receptors.

The concept of activation in the absence of agonists has been demonstrated for many GPCRs and is now solidified as one of the principal aspects of GPCR signaling. In this chapter, we review how dopamine receptors demonstrate this ability. Although difficult to prove in vivo due to the presence of endogenous dopamine and lack of subtype-selective inverse agonists and "pure" antagonists (neutral ligands), in vitro assays such as measuring intracellular cAMP, [(35)S]GTPγS binding, and [(3)H]thymidine incorporation have uncovered the constitutive activation of D1- and D2-class receptors. Nevertheless, because of limited and inconsistent findings, the existence of constitutive activity for D2-class receptors is currently not well established. Mutagenesis studies have shown that basal signaling, notably by D1-class receptors, is governed by the collective contributions of transmembrane domains and extracellular/intracellular loops, such as the third extracellular loop, the third intracellular loop, and C-terminal tail. Furthermore, constitutive activities of D1-class receptors are subjected to regulation by kinases. Among the dopamine receptor family, the D5 receptor subtype exhibits a higher basal signaling and bears resemblance to constitutively active mutant forms of GPCRs. The presence of its constitutive activity in vivo and its pathophysiological relevance, with a brief mention of other subtypes, are also discussed.