Associate editor: H. Bönischβ-1 and β-2 adrenoceptor polymorphisms: Functional importance, impact on cardiovascular diseases and drug responses1
Introduction
β-1 and β-2 adrenoceptors (AR), targets of the endogenous catecholamines noradrenaline and adrenaline, play a pivotal role in regulation of the activity of the sympathetic nervous system. β-1 AR are expressed in the heart where they mediate increases in heart rate and contractility, in the kidney where they mediate release of renin and, by this, activation of the renin–angiotensin–aldosterone system and in adipocytes where they mediate lipolysis (Brodde & Michel, 1999). β-2 AR are abundantly expressed on bronchial and vascular smooth muscle cells where they mediate bronchodilation and vasodilation (Guimaraes & Moura, 2001). They are also expressed in the heart and can mediate positive inotropic and chronotropic effects, but to a lesser extent than do β-1 AR, and are found on glands, lymphocytes and hepatocytes.
Thus, β-1 and β-2 AR are involved in manifold effects of the sympathetic nervous system and might be, therefore, involved pathophysiologically in cardiovascular diseases; moreover, they are often used as targets for drug treatment of cardiovascular diseases. In fact, β-1 AR agonists, such as dobutamine, are often used to acutely give the failing heart inotropic support, and β-2 AR agonists are frequently used in therapy of asthma. In addition, β-1 and β-1 and β-2 AR antagonists (β AR blocker) are first line drugs in treatment of hypertension, stable and unstable angina, acute and post myocardial infarction, ventricular and supraventricular arrhythmias and chronic heart failure (CHF).
It has been known for a very long time that β-1 and β-2 AR responses to drug treatment exhibit marked interindividual variability within the human population. Since the discovery that β-1 AR (Maqbool et al., 1999, Mason et al., 1999, Tesson et al., 1999, Börjesson et al., 2000) and β-2 AR (Green et al., 1993, Reihsaus et al., 1993, Green et al., 1994) are polymorphic, numerous attempts have been made to find out whether these polymorphisms might be, at least partly, responsible for the marked interpatient variability in the cause of cardiovascular diseases and in responses to β AR drug treatment. The aim of this review is therefore to discuss the possible pathophysiological importance of β-1 and β-2 AR polymorphisms for cardiovascular diseases and their impact on responses to β AR drug treatment.
Section snippets
Functional properties of β-1 adrenoceptor polymorphisms
The β-1 AR is encoded by an intronless gene located on chromosome 10q24–26, consisting of a short 5′ untranslated region (UTR) of 86 bp, an open reading frame that encodes a protein of 477 amino acid residues and 3′ UTR of about 900 bp (Frielle et al., 1987). There are 2 major single nucleotide polymorphisms (SNP) in the human β-1 AR coding region: at position 49 in the amino-terminus of the receptor, a serine (Ser) is substituted by a glycine (Gly; Maqbool et al., 1999, Börjesson et al., 2000)
Functional properties of β-2 adrenoceptor polymorphisms
The human β-2 AR, encoded by an intronless gene, is located on chromosome 5q31–32 (Kobilka et al., 1987). In the β-2 AR coding region, 12 single base substitutions have been identified; 5 of these are nonsynonymous (Arg16Gly, Gln27Glu, Val34Met, Thr164Ile and Ser220Cys; for allele frequencies among different racial/ethnic groups, see Table 6) whereas 7 are synonymous and are unlikely to be functionally significant (Table 6) although Silverman et al. (2003) could show that the SNP +523 might
Summary and conclusion
The data published so far clearly indicate that β-1 AR polymorphisms appear not to be disease-causing genes, neither in hypertension or coronary artery disease nor in heart failure. This appears to be also true for the combination of the α-2CDel AR polymorphism (which can be associated with enhanced release of noradrenaline) and the Arg389 β-1 AR polymorphism: the original finding of Small et al. (2002) that this combination significantly increases the risk of heart failure in African Americans
Acknowledgments
Part of the authors work cited in this review was supported by the Deutsche Forschungsgemeinschaft (Bonn/Germany: grant DFG BR 526/8-1; SFB 598-02, BR526/8-3, BR526/10-1; BR526/12-1), the Deutsche Herzstiftung und the Nationales Genomforschungsnetz (Förderzeichen 01GS0107 to O.-E.B.).
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2021, Biomedicine and PharmacotherapyCitation Excerpt :They are particularly polymorphic receptors extensively investigated to assess an association with interindividual variability in β -blockers response or risk of disease [13]. Most of the studies have focused on genes coding for β1 and β2-AR, especially two SNPs in β1-AR gene (ADRB1): rs1801252 (Ser49Gly) and rs1801253 (Arg389Gly); and rs1042713 (Gly16Arg), rs1042714 (Gln27Glu) in β2-AR gene (ADRB2) [11,13]. In the ADRB1, rs1801252 AG and GG genotypes are related to a higher risk of major adverse events (MACE) in patients treated with β-blockers [14].
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The editors note that after completion of this manuscript Dr. Brodde passed away on October 13th, 2007. His contribution to science, in general, and β-adrenoceptor research, in particular, will be sorely missed.