Multiple D₂ dopamine receptors produced by alternative RNA splicing

Abstract

DOPAMINE receptors belong to a large class of neurotransmitter and hormone receptors that are linked to their signal transduction pathways through guanine nucleotide binding regulatory proteins (G proteins). Pharmacological, biochemical and physiological criteria have been used to define two subcategories of dopamine receptors¹ referred to as D₁ and D₂. D₁ receptors activate adenylyl cyclase² and are coupled with the G_s regulatory protein³. By contrast, activation of D₂ receptors results in various responses including inhibition of adenylyl cyclase⁴, inhibition of phosphatidylinositol turnover⁵, increase in K⁺ channel activity⁶ and inhibition of Ca²⁺ mobilization⁷. The G protein(s) linking the D₂ receptors to these responses have not been identified, although D₂ receptors have been shown to both copurify^8,9 and functionally reconstitute^10,11 with both G_i and G_o related proteins³. The diversity of responses elicited by D₂-receptor activation could reflect the existence of multiple D₂ receptor subtypes, the identification of which is facilitated by the recent cloning of a complementary DNA encoding a rat D₂ receptor¹². This receptor exhibits considerable amino-acid homology with other members of the G protein-coupled receptor superfamily^12,13. Here we report the identification and cloning of a cDNA encoding an RNA splice variant of the rat D₂ receptor cDNA¹². This cDNA codes for a receptor isoform which is predominantly expressed in the brain, and contains an additional 29 amino acids in the third cytoplasmic loop, a region believed to be involved in G protein coupling.