Comparative pharmacological and functional analysis of the human dopamine D-4.2 and D-4.10 receptor variants

The human dopamine D-4 receptor is a D-2-like receptor which is a target fo r most common neuroleptics. Previous investigations have shown that this re ceptor displays a large polymorphic variation in the third intracellular lo op 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 pharmacologica l differences have been reported for the most common variants of this recep tor (D-4.2, D-4.4 and D-4.7), although the D-4.7 was reported by us to disp lay a slightly lower potency for dopamine in functional assays. Direct phar macological and functional comparison of the longest and shortest variants in this study suggest no major discrepancies in pharmacological or function al profile between both receptors, Both receptors display, on average, a 15 -fold and 90-fold lower potency for epinephrine and norepinephrine, respect ively, compared with dopamine. We observed small increases in functional po tency and affinity for dopamine and quinpirole at the D-4.10 receptor varia nt compared with the D-4.2 receptor. Our data indicate that there is no dir ect relationship between the length of the polymorphism and changes in phar macology or functional activity. These findings are a suitable caution agai nst the arbitrary pooling of D-4 receptor VNTR genotypes in genetic studies , based on length. Pharmacogenetics 9:561-568 (C) 1999 Lippincott Williams & Wilkins.