Functional analysis of the human D sub(2) dopamine receptor missense variants

• Published in: The Journal of biological chemistry Vol. 271; no. 42; pp. 26013 - 26017
• Main Authors: Cravchik, A, Sibley, DR, Gejman, P V
• Format: Journal Article
• Language: English
• Published: 01.10.1996
• ISSN: 0021-9258

The human dopamine D sub(2) receptor gene (DRD2) has three polymorphic variants that predict the amino acid substitutions Val super(96) arrow right Ala, Pro super(310) arrow right Ser, and Ser super(311) arrow right Cys in the receptor protein. We have investigated the ligand binding and signal transduction properties of these human D sub(2) receptor variants by stably expressing them in cultured mammalian cells. The Cys super(311) and Ser super(310) variants of the human D sub(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 super(310), Ser super(311)). Despite this difference, the Cys super(311) and Ser super(310) variants couple to G proteins in CHO-K1 (Chinese hamster ovary) cells. The impairment of the Cys super(311) and Ser super(310) variants to inhibit cAMP levels thus appears to result from a reduced ability of those variant receptors to activate the appropriate G sub(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 sub(2) receptor blocking drugs in the treatment of schizophrenia and other psychiatric disorders.