B Adrenergic Receptor b2AR

The human b2AR is a member of the G-protein-linked seven-transmembrane domain receptor family. b2ARs are of particular interest because the sequence of the human b2AR gene (ADRB2) is highly variable, giving rise to a coding region with numerous polymorphisms (36,37). The human b2AR is encoded by an intronless gene located on chromosome 5. Four amino acid polymorphisms have been reported within the ADRB2 gene; all are single-base substitutions. The two common polymorphisms in the extracellular domain of the ADRB2 gene, Arg16Gly and Gln27Glu, appear to have functional significance when exposed to exogenously administered b2AR agonists. For example, in transfected Chinese hamster fibroblasts and in primary cultured smooth muscle cells expressing these variants, the Gly16 version of the receptor undergoes enhanced agonist-promoted downregulation of receptor number, as compared with the Arg16 form of the receptor. By contrast, Glu27

b2AR is relatively resistant to such downregulation as compared with the Gln27 form of the receptor, but only when co-expressed with Arg16 (37,38). The third polymorphism in the intercellular domain, Thr164Ile, also has several functional effects, which include lower binding affinities for agonists and deficient coupling of the receptor to adenylate cyclase. Transgenic mice expressing Thr164Ile variant receptor targeted to the heart manifested impaired myocardial signaling and function (39).

b2AR polymorphisms have been implicated in the pathogenesis of essential hypertension, both on the basis of evidence suggesting altered b2-mediated vasodilatation (40-42) and on the basis of linkage studies (43). Some studies (44), but not all (45), have demonstrated the relationship between certain b2AR polymorphic alleles and hypertension, presumably because the expression of these receptor forms exerts a vasodilatory influence on vascular smooth muscle. The risk appears to be greater for those possessing Gly16 and Glu27 alleles, the latter (Glu27 allele) having an odds ratio for occurrence of hypertension of 1.80 (44). Given the massive heterogeneity of hypertension, it is not surprising to find that b2AR polymorphisms are responsible only for exerting a relatively small effect. Several studies have associated the Ile164 allele with heart failure (46). Indeed, individuals with the Ile164 receptor experienced an increased risk of either death or transplant compared with the Thr164 homozygotes. A subsequent study measured exercise capacity and showed substantially reduced exercise capacity in Ile164 allele carriers (47). Importantly, several studies have also demonstrated a relationship between ADRB2 genotype and some measure of vascular relaxation in response to agonist infusion (41,42,48,49). In a study by Brodde et al. (50) of healthy subjects, the Ile164 allele carriers showed decreased responsiveness (heart rate and systolic time interval) to b2AR agonist infusions as compared with Thr164 homozygotes. This suggests that the alternative alleles of the Ile/Thr164 polymorphism have physiologic effects even in the absence of a disease phenotype, such as heart failure. The clinical implications are that, in patients carrying the Thr164Ile b2AR polymorphism (Ile164 allele), the therapeutic efficacy of such treatment with b2AR agonists might initially be lower than in patients with the wild-type genotype (Thr/Thr). However, with ongoing treatment (and thus b2AR desen-sitization), this disadvantage might disappear because desensitization in these patients is likely to be less than in wild-type b2AR patients.

These polymorphisms have also been extensively evaluated in respiratory disease: these effects are discussed in detail in the relevant chapter 6 in this book.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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