Genetic determinants of dopaminergic activity: potential role in blood pressure regulation

Dopamine (DA) availability for precursor function and peripheral biological action is dependent on synthesis and inactivation enzymes, most of them have been cloned and located. An aromatic acid decarboxylase (AADC) defect has been reported in male homozygotic twins. The syndrome of complete dopamine-beta-hydroxylase deficiency with orthostatic hypotension and very high DA contributes to our understanding of the role of DA as a catecholamine with a peripheral biological action of its own. X-linked isolated monoamine oxidase A gene deficiency represents a marked disturbance of monoamine metabolism. The genes of the two major extraneuronal DA-metabolizing enzymes--catechol-O-methyl-transferase and phenolsulfotransferase (PST)-have also been defined. Of particular interest is a bidirectional shuttle system between the PST and sulfatase which have been cloned and located. DA, highly sulfoconjugated via PST, yields DA sulfate which is reconvertible by sulfatase to Free DA. A defect of sulfatase catalyzing this process results in a predominance of DA as biologically inactive DA sulfate and so attenuates the DA action. Enzymatic defects of DA synthesis and metabolism are thus genetic modulators of DA action.