The dopamine D1C receptor: Expansion and origin of the dopamine D1 receptor family

Dopamine D1 receptors are implicated in several neuronal processes including motivation, reward, cognition and working memory. To date, two D1-like receptors that activate the same second messenger system, the D1/D1A and D5/D1B receptors, have been isolated from mammals. The heterogeneity of dopamine D1 receptor-mediated events, however, may not be completely reconciled by the presence of only two dopamine D1-like receptors, as biochemical, behavioural and pharmacological data have alluded to the existence of other putative subtypes. This work provides direct molecular evidence for the existence of at least three distinct D1-like receptor genes, termed D1A, D1B and D1C, from a number of nonmammalian vertebrate species. These were classified on the basis of phylogenetic, molecular, pharmacological, and functional criteria. While all three subtypes stimulated the ac cumulation of cAMP in expressed cells, D1A, D1B and D1C receptor chimeras in which the highly divergent carboxyl termini were interchanged revealed a modulatory influence of this domain in determining functional responsiveness. The evolutionary emergence and expansion of the D1-like receptor gene family were further investigated from representatives of early diverging phyla. The isolation of an adenylyl-cyclase activating dopamine receptor from Drosophila melanogaster with poor affinity for classical D1-like benzazepine agents indicates that high affinity benzazepine pharmacology arose after the separation of vertebrates and invertebrates. The characterization of a D1-like receptor from amphioxus, a cephalochordate and sister species to vertebrates, indicates that the gene duplication event leading to D1-like diversity occurred with the appearance of early vertebrates. These studies have provided insight into the molecular phylogenetic history and diversity of the dopamine D1-like receptor family. More importantly, the cloning of the D1C receptor lends strong support to the contention that additional D1-like receptor gene products 0may be present in mammals which allow for the expression of the full spectrum of dopamine D1-like receptor mediated events.