Modulation of Intracellular Cyclic AMP Levels by Different Human Dopamine D4 Receptor Variants

Abstract

To investigate whether polymorphic forms of the human dopamine D4 receptor have different functional characteristics, we have stably expressed cDNAs of the D4 .2, D4 .4, and D4 .7 isoforms in several cell lines . Chinese hamster ovary CHO-K1 cell lines expressing D4 receptor variants displayed pharmacological profiles that were in close agreement with previous data from transiently expressed D4 receptors in COS-7 cells . Dopamine stimulation of the D4 receptors resulted in a concentration-dependent inhibition of the forskolin-stimulated cyclic AMP (cAMP) levels . The potency of dopamine to inhibit cAMP formation was about twofold reduced for D4 .7 (EC so of -37 nM) compared with the D4 .2 and D4 .4 variants (EC SO of -16 nM) . Antagonists block the dopamine-mediated inhibition of cAMP formation with a rank order of potency of emonapride > haloperidol = clozapine > raclopride . There was no obvious correlation between the efficacy of inhibition of forskolin-stimulated cAMP levels and the D4 subtypes . Dopamine could completely reverse prostaglandin E 2 -stimulated cAMP levels for all three D4 receptor variants . Deletion of the repeat sequence does not affect functional activity of the receptor . The data presented indicate that the polymorphic repeat sequence causes only small changes in the ability of the D4 receptor to block cAMP production in CHO cells . Key Words : Dopamine receptors-D4-Cyclic AMP-Variants .

European clinical guidelines for hyperkinetic disorder ? first upgrade

“…While the 10-repeat allele of DAT1 has been associated with an increased expression of the transporter [49,99], the 7-repeat allele of DRD4 seems to encode a receptor that is subsensitive to dopamine [5].…”

The human dopamine D4 receptor repeat sequences modulate expression

“…6,8,13 While the different variants show no difference in their ability to couple to Gai/o 12 proteins, there is a small two-to three-fold difference in potency between the D4.7 and the D4.4, D4.2 and D4.9 variants in coupling to adenylyl cyclase. 13,22 The objective of this study was to explore whether the repeat sequences can modulate expression by integrating it at various positions in a luciferase reporter vector. The results of the experiments suggest that the D4 repeat sequences can modulate expression and that the repeat variants may affect RNA stability and/or translational efficiency differently.…”

DAT1, DRD4, and DRD5 polymorphisms are not associated with ADHD in Dutch families

“…The dopamine receptor D4 gene (DRD4) has a VNTR polymorphism in the third exon, which is part of the third intracellular loop of the receptor, and may therefore have functional relevance [Asghari et al, 1995;Schoots and Van Tol, 2003]. Recent meta-analyses confirmed that the 7-repeat allele increased the risk of developing ADHD 1.4-2.0 times [Faraone et al, 2001;Maher et al, 2002].…”