Coupling of D1 and D5 dopamine receptors to multiple G proteins: Implications for understanding the diversity in receptor-G protein coupling.

Abstract

Dopamine receptors are a subclass of the super family of G protein-coupled receptors, that transduce their effects by coupling to specific G proteins. Within the dopamine receptor family, the adenylyl cyclase stimulatory receptors include the D1 and D5 subtypes. The D1 and D5 dopamine receptors are genetically distinct, sharing >80% sequence homology within the highly conserved seven transmembrane spanning domains, but displaying only 50% overall homology at the amino acid level. When expressed in transfected GH4C1 rat pituitary cells, both D1 and D5 receptors stimulate adenylyl cyclase and have identical affinities toward dopaminergic agonists and antagonists. In order to analyze specific signaling pathways mediated by activation of either D1 or D5 receptors, we have identified the G proteins that are coupled to these receptors. Through functional analyses and competition binding studies, and from immunoprecipitation techniques, using antisera against the various alpha subunits of G proteins, we have established that both D1 and D5 receptors couple to G(s)alpha. In addition, D1 receptors are also coupled to G(o)alpha. Since G(o)alpha has been implicated in the regulation of Ca2+, K+, and Na+ channels, this finding would suggest that D1 receptors can mediate the functional activity of these ion channels. There is also evidence to indicate that D5 receptors couple to G(z)alpha, a novel G protein abundantly expressed in neurons. Thus, despite similar pharmacological properties, such differential coupling of D1 and D5 receptors to G proteins other than G(s)alpha, indicates that dopamine can transduce varied signaling responses upon the simultaneous stimulation of both these receptors.