Pharmacological analysis of human D1 AND D2 dopamine receptor missense variants.

Drugs targeting dopamine receptors have been the focus of much research over the past 30 years, in large part because of their role in treating multiple pathological conditions including Parkinson's disease, schizophrenia, Tourette's syndrome, and hyperprolactinemia. Missense mutations in G protein-coupled receptors (GPCRs) can alter basal and/or ligand-induced signaling, which in turn can affect individuals' susceptibility to disease and/or response to therapeutics. To date, five coding variants in the human D1 receptor (hD1R; T37P, T37R, R50S, S199A, and A229T) and three in the human D2 receptor (hD2R; P310S, S311C, and T351A) have been reported in the NCBI single nucleotide polymorphism database.

Identification of amino acid determinants of dopamine 2 receptor synthetic agonist function.

The human dopamine 2 receptor (hD2R) modulates locomotor activity, hormone secretion, and neuropsychiatric function. Current knowledge of the hD2R structure is in large part derived from mutagenesis studies and molecular pharmacologic analysis together with homology modeling using bovine rhodopsin as a template. In this study, we utilized comparison of the Drosophila D2-like receptor (DD2R) with the hD2R as a novel approach for identifying candidate amino acids that are determinants of ligand potency and/or efficacy.