Comparative pharmacological and functional analysis of the human dopamine D4.2 and D4.10 receptor variants.
The human dopamine D4 receptor is a D2-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 (D4.2 and D4.10). No major pharmacological differences have been reported for the most common variants of this receptor (D4.2, D4.4 and D4.7), although the D4.7 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 D4.10 receptor variant compared with the D4.2 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 D4 receptor VNTR genotypes in genetic studies, based on length.
Jovanovic
V
V
Laboratory of Molecular Neurobiology, Centre for Addiction and Mental Health, Clarke Division, and University of Toronto, Ontario, Canada.
Guan
H C
HC
Van Tol
H H
HH
D000595:Amino Acid Sequence; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D018491:Dopamine Agonists / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology; D014644:Genetic Variation; D006801:Humans; D018598:Minisatellite Repeats; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009638:Norepinephrine / Q000494:pharmacology; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D019257:Quinpirole / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D050638:Receptors, Dopamine D4; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D014150:Antipsychotic Agents; C493599:DRD4 protein, human; D018491:Dopamine Agonists; D017448:Receptors, Dopamine D2; D011994:Recombinant Proteins; D050638:Receptors, Dopamine D4; D019257:Quinpirole; D004298:Dopamine; D009638:Norepinephrine; D004837:Epinephrine