Cloning, molecular characterization, and chromosomal assignment of a gene encoding a second D1 dopamine receptor subtype: differential expression pattern in rat brain compared with the D1A receptor.

Abstract

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...

神经细胞中多巴胺d1和d5受体不同亚细胞分布和胞内转运的特性

“…It has been reported that the substituted mutation of a hydrophobic motif, or the truncated mutation of C-terminus would disturb the cell surface targeting of D1R [22,23] . The two D1-like receptor subtypes, D1R and D5R, exhibit more diversity in their C-termini amino acid sequence than that in transmembrane segments [4][5][6][7] .…”

“…Potential mechanisms have been attributed to the different receptor subtypes, their differential affinities to agonist and their differential cellular or subcellular distributions [1,5,6,[31][32][33][34] .…”

“…With the advant of the D1 selective ligands, D1-like receptors are distinguished from the D2-like receptors [1][2][3] . Then D1-like receptor subtypes, D1 receptor (D1R) and D5 receptor (D5R), are further identified in mammalian brain by cDNA cloning [4][5][6][7] . However, currently there is no selective ligand available to distinguish between D1R and D5R.…”

“…Recently, accumulating evidences have indicated that D1R and D5R play the distinct roles in brain: (1) D5R shows affinity to dopamine ten-fold higher than D1R [5,6] ; (2) D1R knockdown in brain prevents the contralateral rotations of 6-hydroxdopamine-lesioned rats induced by D1 agonist, whereas D5R knockdown enhances such rotation behavior [8] .…”

Interactions of the Novel Antipsychotic Aripiprazole (OPC-14597) with Dopamine and Serotonin Receptor Subtypes

“…Received April 17, 1998; revised August 27, 1998; accepted September 21, 1998. (Zhou et al 1990;Monsma et al 1990;Sunahara et al 1990;Dearry et al 1990) and D 1B (Tiberi et al 1991) or D 5 (Sunahara et al 1991], both of these linked functionally to stimulation of cAMP synthesis, and preferentially recognizing 1-phenyl-tetrahydrobenzazepines (e.g., SCH23390). The D 2 -like receptors come from at least three genes and include multiple splice variants.…”