Functional analysis of the human D-2 dopamine receptor missense variants

The human dopamine D-2 receptor gene (DRD2) has three poly-morphic 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.