Functional Analysis of the Human D2 Dopamine Receptor Missense Variants

• Published in: The Journal of biological chemistry Vol. 271; no. 42; pp. 26013 - 26017
• Main Authors: Cravchik, A, Sibley, D R, Gejman, P V
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 18.10.1996
• Subjects: Animals; Binding, Competitive; Cell Line; Colforsin - pharmacology; Cricetinae; Cricetulus; Cyclic AMP - biosynthesis; Dopamine - metabolism; Dopamine Agonists - metabolism; Female; Humans; Kinetics; Ovary - metabolism; Polymorphism, Genetic; Receptors, Dopamine D2 - genetics; Receptors, Dopamine D2 - metabolism; Spiperone - analogs & derivatives; Spiperone - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.271.42.26013

The human dopamine D 2 receptor gene ( DRD2 ) has three polymorphic variants that predict the amino acid substitutions Val 96 → Ala, Pro 310 → Ser, and Ser 311 → Cys in the receptor protein. We have investigated the ligand binding and signal transduction properties of these human D 2 receptor variants by stably expressing them in cultured mammalian cells. The Cys 311 and Ser 310 variants of the human D 2 receptor, which involve substitutions located in the third cytoplasmic loop, were markedly less effective in inhibiting cAMP synthesis than the most prevalent form (Pro 310 , Ser 311 ). Despite this difference, the Cys 311 and Ser 310 variants couple to G proteins in CHO-K1 (Chinese hamster ovary) cells. The impairment of the Cys 311 and Ser 310 variants to inhibit cAMP levels thus appears to result from a reduced ability of those variant receptors to activate the appropriate G i -like protein. The demonstration of substantial functional differences between DRD2 gene variants found in the human population might have important pharmacological implications given the widespread use of D 2 receptor blocking drugs in the treatment of schizophrenia and other psychiatric disorders.