Comparative pharmacological and functional analysis of the human dopamine D4.2 and D4.10 receptor variants

The human dopamine D-4 receptor is a D-2-like receptor which is a target for most common neuroleptics. Previous investigations have shown that this receptor displays a large polymorphic variation in the third intracellular loop involving a variable number of direct imperfect tandem repeats (VNTR) of 16 amino acids. The shortest and longest repeat variants reported to date contain two and 10 repeat units (D-4.2 and D-4.10). No major pharmacological differences have been reported for the most common variants of this receptor (D-4.2, D-4.4 and D-4.7), although the D-4.7 was reported by us to display a slightly lower potency for dopamine in functional assays. Direct pharmacological and functional comparison of the longest and shortest variants in this study suggest no major discrepancies in pharmacological or functional profile between both receptors, Both receptors display, on average, a 15-fold and 90-fold lower potency for epinephrine and norepinephrine, respectively, compared with dopamine. We observed small increases in functional potency and affinity for dopamine and quinpirole at the D-4.10 receptor variant compared with the D-4.2 receptor. Our data indicate that there is no direct relationship between the length of the polymorphism and changes in pharmacology or functional activity. These findings are a suitable caution against the arbitrary pooling of D-4 receptor VNTR genotypes in genetic studies, based on length. Pharmacogenetics 9:561-568 (C) 1999 Lippincott Williams & Wilkins.