Sympathoneural and adrenomedullary functional effects of ??2C-adrenoreceptor gene polymorphism in healthy humans
ABSTRACT alpha2-Adrenoreceptors restrain sympathetic nervous outflows and inhibit release of noradrenaline from sympathetic nerves. In-frame deletion of the alpha2C-adrenoreceptor subtype (alpha2CDel322-325) increases the risk of congestive heart failure. Increased delivery of catecholamines to cardiovascular receptors might explain this increased risk.
Twenty-nine healthy African-Americans genotyped for alpha2-adrenoreceptor subtype polymorphisms underwent 3H-noradrenaline and 3H-adrenaline intravenous infusion and arterial blood sampling for measurements of rates of entry of endogenous noradrenaline and adrenaline into arterial plasma (total body spillovers) by the tracer dilution technique. Eleven subjects were homozygotes for the alpha2CDel322-325 polymorphism, nine heterozygotes, and nine non-carriers. Subjects were studied during supine rest and during and after i.v. infusion of the alpha2-adrenoreceptor antagonist, yohimbine.
At rest, homozygotes for the alpha2CDel322-325 polymorphism had higher total body noradrenaline spillover than did heterozygotes (t=2.90, df=18, P=0.023) or non-carriers (t=3.22, df=18, P=0.010). Adrenaline spillover was higher in homozygotes than non-carriers (t=2.61, df=18, P=0.045). Administration of yohimbine produced larger, more sustained increments in noradrenaline spillover, heart rate, and anxiety in homozygotes than in the other groups.
In healthy people, alpha2CDel322-325 polymorphism is associated with increased sympathetic nervous and adrenomedullary hormonal activities, both during supine rest and during pharmacologically evoked catecholamine release. Polymorphisms of the alpha2C-adrenoreceptor may help explain individual differences in predisposition to a variety of disorders of catecholaminergic function, such as cardiovascular disorders, depression or anxiety disorders.
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- "The lack of clear genetic linkages may be due to the finding that both variant forms of α2 ARs exist as multiple haplotypes, and expression of specific haplotypes may be more important determinants of cardiovascular disease risk (Small et al. 2004; Small et al. 2006). Despite the lack of a clear linkage to cardiovascular disease, it has been demonstrated that human α2C Δ322- 325 AR homozygotic volunteers have the pathophysiological trait of increased sympathoneural drive (Neumeister et al. 2005). Subsequent pharmacological analysis of α2C Δ322-325 ARs using intact HEK293 cells suggested no loss-of-function phenotype, suggesting that if this variant form did have a linkage to pathophysiological conditions (such as increased sympathoneural drive), other cellular mechanisms of receptor dysfunction must play a role. "
ABSTRACT: Various naturally occurring polymorphic forms of human G protein-coupled receptors (GPCRs) have been identified and linked to diverse pathological diseases, including receptors for vasopressin type 2 (nephrogenic diabetes insipidus) and gonadotropin releasing hormone (hypogonadotropic hypogonadism). In most cases, polymorphic amino acid mutations disrupt protein folding, altering receptor function as well as plasma membrane expression. Other pathological GPCR variants have been found that do not alter receptor function, but instead affect only plasma membrane trafficking (e.g., delta opiate and histamine type 1 receptors). Thus, altered membrane trafficking with retained receptor function may be another mechanism causing polymorphic GPCR dysfunction. Two common human α2A and α2C adrenergic receptor (AR) variants have been identified (α2A N251K and α2C Δ322-325 ARs), but pharmacological analysis of ligand binding and second messenger signaling has not consistently demonstrated altered receptor function. However, possible alterations in plasma membrane trafficking have not been investigated. We utilized a systematic approach previously developed for the study of GPCR trafficking motifs and accessory proteins to assess whether these α2 AR variants affected intracellular trafficking or plasma membrane expression. By combining immunofluorescent microscopy, glycosidic processing analysis, and quantitative fluorescent-activated cell sorting (FACS), we demonstrate that neither variant receptor had altered intracellular localization, glycosylation, nor plasma membrane expression compared to wild-type α2 ARs. Therefore, pathopharmacological properties of α2A N251K and α2C Δ322-325 ARs do not appear to be due to altered receptor pharmacology or plasma membrane trafficking, but may involve interactions with other intracellular signaling cascades or proteins.Archiv für Experimentelle Pathologie und Pharmakologie 03/2014; 387(6). DOI:10.1007/s00210-014-0972-6 · 2.36 Impact Factor
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- "However, the contribution of genetic factors to the ethnic differences in health is often very small and the results are often difficult to replicate (Cooper and Zhu 2001, Cruickshank et al. 2001, Cooper 2003, Li et al. 2006). For example, sequence variations in the human a 2 adrenergic receptor genes (ADRA2A and ADRA2C) were implicated as a cause of hypertension in African-American subjects (Lockette et al. 1995, Neumeister et al. 2005). From a stratified random population sample of 1767 subjects, however, Li et al. (2006) found no association of either variant with hypertension in African-Americans. "
ABSTRACT: Chronic diseases such as cardiovascular diseases (CVD) are major health problems in most ethnic minority and migrant populations living in high income countries. By the same token, CVD is a looming threat that is creating a double burden in most of the countries where these populations originate from. The causes of the rising burden are unclear, but they are likely to be multifaceted. Traditionally, ethnicity and health research have mostly concentrated on comparing the health of ethnic minority groups with the majority populations of the countries in which they live. This is an important area of research which illuminates ethnic inequalities in health. However, a few studies on international comparisons show that a lot can be learned from comparing similar ethnic groups living in different industrialised countries. Equally, comparing ethnic minority and migrant populations to similar populations in their countries of origin will generate new knowledge about factors that predispose them to poor health outcomes. Thus, to make progress in the field of ethnicity and health research, we need a new conceptual framework that simultaneously studies migrant/ethnic groups in the country of settlement, in similar countries of settlement, and in the countries of ancestral origin. Such studies need to go beyond the commonest design of cross-sectional studies to include more cohort studies, interventions and linkage studies. This article discusses (1) the burden of CVD in ethnic minority and migrant populations; (2) approaches to understanding predisposing factors; and (3) application of the results to give insight into the potential threats that their countries of origin are likely to face.Ethnicity and Health 12/2012; 17(6):579-596. DOI:10.1080/13557858.2012.730607 · 1.28 Impact Factor
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- "Yohimbine, a drug that blocks the a2 receptors (i.e., a receptor antagonist), increases alcohol self-administration and induces reinstatement of alcohol seeking (Le et al. 2005; Marinelli et al. 2007). The recent finding that an a2c receptor polymorphism (Del322-325) reduces feedback inhibition of sympathetic NE release (Neumeister et al. 2005) as well as evidence from studies in mice bred to have an inactivated a2c receptor (i.e., knockout mice) (Sallinen et al. 1999), suggest that interventions targeting this receptor might modulate stress and anxiety responses. "
ABSTRACT: Acute and chronic stress-related mechanisms play an important role in the development of addiction and its chronic, relapsing nature. Multisystem adaptations in brain, body, behavioral, and social function may contribute to a dysregulated physiological state that is maintained beyond the homeostatic range. In addition, chronic abuse of substances leads to an altered set point across multiple systems. Resilience can be defined as the absence of psychopathology despite exposure to high stress and reflects a person's ability to cope successfully in the face of adversity, demonstrating adaptive psychological and physiological stress responses. The study of resilience can be approached by examining interindividual stress responsibility at multiple phenotypic levels, ranging from psychological differences in the way people cope with stress to differences in neurochemical or neural circuitry function. The ultimate goal of such research is the development of strategies and interventions to enhance resilience and coping in the face of stress and prevent the onset of addiction problems or relapse.01/2012; 34(4):506-15.