Human Genetics of Plasma Dopamine Β-Hydroxylase Activity: Applications to Research in Psychiatry and Neurology
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Psychopharmacology (2004) 174: 463–476 DOI 10.1007/s00213-004-1840-8 REVIEW J. F. Cubells . C. P. Zabetian Human genetics of plasma dopamine β-hydroxylase activity: applications to research in psychiatry and neurology Received: 5 August 2003 / Accepted: 5 February 2004 / Published online: 16 April 2004 # Springer-Verlag 2004 Abstract Rationale: Norepinephrine (NE) is a key ergic dysfunction to a variety of symptoms in Parkinson’s neurotransmitter in the central and peripheral nervous disease and other degenerative neurological disorders. systems. Dopamine β-hydroxylase (DβH) catalyzes the Conclusions: A model is proposed, in which lower levels synthesis of NE from dopamine (DA) and occurs in the of DβH protein may lead to elevated ratios of DA to NE. plasma as a stable heritable trait. Studies of this trait have This model may explain associations between lower been useful in psychiatric and neurological research. plasma DβH activity and vulnerability to psychotic Objective: To selectively and critically review the litera- symptoms. Genotype-controlled analysis of plasma DβH ture on plasma DβH, and on recent progress under- holds promise for promoting further progress in research standing the molecular genetic basis for its inheritance. on psychiatric and neurological disorders. Based on this review, directions for future research in psychiatry and neurology will be suggested. Methods: Keywords Catecholamines . Norepinephrine . We selectively review the literature on the biochemical and Quantitative trait locus . Sympathetic nervous system . molecular genetics of plasma DβH activity, as well as Psychosis . Depression . Alcoholism . Attention deficit research on plasma and cerebrospinal fluid (CSF) DβHin hyperactivity disorder . Parkinson’s disease . Hypotension psychiatric and neurological disorders. Results: Strong evidence implicates DBH, the structural locus encoding DβH enzyme, as the major quantitative trait locus influencing plasma DβH activity, with one single nucle- Norepinephrine (NE) mediates many important functions otide polymorphism (SNP) accounting for up to 50% of in the central and peripheral nervous systems. It is the the variance. Mutations at DBH appear to be responsible major post-ganglionic neurotransmitter of the sympathetic for the rare syndrome of DβH deficiency. Some nervous system (SNS), where its release regulates vascular biochemical and genetic studies suggest associations tone and cardiac contractility, among other vital functions. between low plasma or CSF DβH and psychotic symp- NE is also a hormone and a precursor for epinephrine in toms in several psychiatric disorders. Studies combining neurosecretory cells of the adrenal medulla. Both genotyping at DBH with biochemical measurement of hormones contribute to “fight–flight” endocrine responses plasma DβH have proven useful in studies of schizophre- such as vascular and cardiac responses, and mobilization nia, cocaine-induced paranoia (CIP), depression, attention of glucose from hepatic glycogen stores. In the central deficit hyperactivity disorder, and alcoholism. Such nervous system, NE is localized within several neuronal studies may also elucidate the contribution of noradren- populations in the hindbrain and midbrain. The locus ceruleus (LC) is the largest of these, and accounts for most J. F. Cubells (*) of the noradrenergic innervation of the forebrain. Norad- Department of Psychiatry, Yale University School of Medicine renergic neurons of the LC project widely throughout the and VA Connecticut Health Care System, brain, innervating virtually every gray-matter region. 950 Campbell Avenue, Numerous sub-cortical brain areas, as well as the neocor- West Haven, CT 06516, USA e-mail: [email protected] tex, are richly innervated by NE-containing fibers (Amaral Tel.: +1-203-937-4943 and Sinnamon 1977; Moore and Bloom 1979; Foote et al. Fax: +1-203-937-3897 1983). NE thus contributes to regulation of many centrally mediated physiological, cognitive, and behavioral func- C. P. Zabetian Department of Neurology, University of Washington School of tions (Grace et al. 1998; Arnsten 2000a,b). Medicine and VA Puget Sound Health Care System, Seattle, WA 98108, USA 464 NE is a target for medication treatment of many human diseases, and may also mediate pathophysiological processes. For example, medications influencing NE- mediated transmission are widely used in treatment of medical illnesses such as hypertension and myocardial ischemia (Esler et al. 2001); neurological conditions such as sleep disorders (Mitler et al. 1993), neurodegenerative disorders (Schirger et al. 1981), and migraine headaches (Holroyd et al. 1991); and psychiatric disorders such as major depressive disorder (Anand and Charney 2000), attention deficit-hyperactivity disorder (ADHD; Arnsten 2000a), and anxiety disorders (Kent et al. 2002). Recent Fig. 1 Diagram of NE synthesis within a hypothetical noradrener- data suggest that functional genetic variation in the β1 and gic neuron, showing localization of DβH within synaptic vesicles. α2c adrenergic receptor proteins modifies risk for poor Dopamine is synthesized in the cytoplasm, and then transported into outcomes in cardiovascular disease (Small et al. 2002). the vesicle by the vesicular monoamine transporter, which derives its energy from the proton gradient across the vesicular membrane. One of the premises underlying the present review is that Abbreviations: tyr, tyrosine; TH, tyrosine hydroxylase; AADC, genetic studies of other NE-related proteins will similarly aromatic L-amino acid decarboxylase elucidate medical, neurological and psychiatric disorders. We focus on DBH, the locus encoding dopamine β- hydroxylase (DβH), the enzyme catalyzing the synthesis vesicular proteins are released from sympathetic nerve of NE from dopamine (DA; Kaufman and Friedman terminals (Smith et al. 1970; Weinshilboum et al. 1971), 1965). and that DβH can be assayed in plasma (Weinshilboum As schematized in Fig. 1,DβH is specifically expressed and Axelrod 1971) led to attempts to use plasma DβH in NE-containing neurons; it is the only catecholamine- levels as an index of sympathetic noradrenergic tone. synthetic enzyme localized within synaptic vesicles, where However, it quickly became clear that plasma DβH levels it occurs in both soluble and membrane-bound forms were quite stable within individuals, even during strenuous (Stewart and Klinman 1988). As a result of its vesicular exercise and cold pressor stimulation, both known to localization, DβH is released together with NE and other produce large increases in circulating catecholamines vesicular contents during synaptic transmitter release (Winer and Carter 1977; Peronnet et al. 1985). The lack (Smith et al. 1970; Weinshilboum et al. 1971). Some of substantial acute changes in plasma DβH levels DβH protein might also be secreted via a constitutive following these stimuli probably reflected the large exocytotic pathway (Oyarce and Fleming 1991). By virtue difference in metabolic kinetics of plasma catecholamines of its secretion into the extracellular space, DβH occurs in versus DβH protein, as the half-life of circulating DβHis the cerebrospinal fluid (CSF), and in plasma or serum (we estimated at 4.2 days in rats (Grzanna and Coyle 1978). henceforth refer to plasma or serum DβH only as plasma Developmental and longitudinal studies show that DβH). Typically, plasma DβH is assayed as enzyme plasma DβH activity is remarkably stable within subjects activity under saturating substrate and co-factor conditions after the age of 5 years (Ogihara et al. 1975; Weinshil- (Nagatsu and Udenfriend 1972), but levels of DβH protein boum 1978; Heiss et al. 1980). In contrast, plasma DβH have also been estimated directly using radioimmune activity varies widely across unrelated individuals (Wein- assay (Dunnette and Weinshilboum 1976;O’Connor et al. shilboum et al. 1973). Robust correlations among levels of 1983, 1994). Since the two sets of measures correlate plasma DβH in first-degree relatives (Weinshilboum et al. strongly (r >0.80: Ebstein et al. 1973; Dunnette and 1973), and nearly perfect correlations between monozy- Weinshilboum 1976;O’Connor et al. 1983), we will use gotic twins (Ross 1973) strongly supported the hypothesis the terms plasma DβH activity and plasma DβH levels that genetic mechanisms contributed to inter-individual interchangeably. The remainder of this paper will review variation in plasma DβH. Population and family genetic recent progress in understanding molecular genetic studies by Weinshilboum et al. (1975) suggested that only mechanisms regulating plasma DβH levels, studies of a few genes accounted for the heritable variation in plasma plasma DβH activity and of DBH genotypes in psychiatric DβH activity. A subgroup of subjects in these studies and neurological disorders, and suggest specific areas of exhibited “very-low” plasma DβH levels, defined as research that may benefit from further genetic and levels below 50 IU/ml in a population distribution ranging biochemical analysis of plasma DβH activity. from approximately 0–2000 nmol/h per ml. Segregation analysis of the very-low DBH trait suggested that individuals exhibiting very low serum DBH activity Overview of past work: plasma DβH is a quantitative were homozygotes carrying an allele at a single hypothe- genetic trait tical locus, which Weinshilboum et al. named “DBHL.” The molecular identity of this locus was unknown at the Weinshilboum (1978) provides a comprehensive review of time. the seminal work on plasma