Multiple DI dopaminergic receptor subtypes have been postulated on the basis of pharmacological, biochemical, and genetic studies. We describe the isolation and characterization of a rat gene encoding a dopamine receptor that is structurally and functionally similar to the D1 dopamine receptor. The coding region, which is intronless, encodes a protein of 475 amino acids (Mr 52,834) with structural features that are consistent with receptors coupled to guanine nucleotide-binding regulatory proteins. The expressed protein binds dopaminergic ligands and mediates stimulation of adenylyl cyclase with pharmacological properties similar to those of the DI dopamine receptor. The gene encoding the human homologue of this receptor subtype is located to the short arm of chromosome 4 (4p16.3), the same region as the Huntington disease gene. In striking contrast to the previously cloned DI receptor, little or no mRNA for the receptor described here was observed in striatum, nucleus accumbens, olfactory tubercle, and frontal cortex. High levels of mRNA for this receptor were found in distinct layers of the hippocampus, the mammillary nuclei, and the anterior pretectal nuclei, brain regions that have been shown to exhibit little or no DI dopamine receptor binding. On the basis of its properties we propose that this dopamine receptor subtype be called DIB1The actions of dopamine were originally thought to be mediated by an interaction with two distinct receptor subtypes: D1 receptors, which were coupled to the stimulation of adenylyl cyclase, and D2 receptors, which were either linked or not linked to the inhibition of adenylyl cyclase (1). Recently, molecular biological approaches have supported and extended this pharmacological classification. At least three different receptor genes code for dopamine receptor subtypes-namely, D1, D2, and D3 (2-9). These receptors belong to the large family of receptors coupled to guanine nucleotide-binding regulatory protein (G protein) and are believed to contain seven membrane-spanning domains (10).Traditionally, the central actions of dopaminergic compounds have been attributed to their interactions with D2 dopamine receptors (11). However, recent studies have indicated that D1 dopamine receptors have important functions in the central nervous system (12). The distribution of D1 receptors in brain has been studied by using the selective ligand SCH 23390. Although this ligand binds to a single class ofreceptor sites, recent evidence has suggested the existence of multiple D1 receptor subtypes (13). For instance, it has been demonstrated (14) that injection of rat striatal mRNA into Xenopus oocytes directs the expression of a D1 dopamine receptor coupled to activation of phospholipase C and phosphatidylinositol phosphate metabolism. Furthermore, dopamine does not stimulate adenylyl cyclase in the amygdala, a tissue known to contain specific binding sites for the radiolabeled Dl-selective antagonist SCT{ 23390 (13). In the periphery, D1 receptors have been shown to stimulate adenyly...
