Trends in Pharmacological Sciences
OpinionPolymorphisms determine β-adrenoceptor conformation: implications for cardiovascular disease and therapy
Introduction
As primary target receptors mediating the effects of the endogenous catecholamines noradrenaline and adrenaline, β-adrenoceptors have a central role in the response of various organs to sympathetic stimulation. Consistent with their important function in physiology, agonists and antagonists at β1- and β2-adrenoceptors have evolved as effective and widely used remedies in various diseases (Table 1).
However, the therapeutic efficacy of β-adrenoceptor agonists and antagonists displays considerable variation among patients. An increasing body of evidence indicates that these interindividual differences in drug response might be due to the highly polymorphic nature of both receptor subtypes. Although consensus seems to form with regard to the role of polymorphisms in drug response, contradictory results have been reported with respect to the relevance of these polymorphisms in disease causation and progression, particularly in complex syndromes such as asthma and heart failure. These discrepancies might be attributed to the small sizes of the cohorts studied and the complex and highly regulated physiological parameters that were analyzed. These problems might partially be circumvented with experimental techniques that more directly assess receptor conformation and drug-induced receptor conformational changes. Here, we summarize the recent progress in the field with regard to our knowledge about structure and ligand-induced conformational changes of the β-adrenoceptors, their determination through receptor polymorphisms and possible consequences for drug therapy.
Section snippets
Functional relevance of β-adrenoceptor polymorphisms
β-adrenoceptors are members of the superfamily of seven-transmembrane-domain G-protein-coupled receptors (GPCRs) with an extracellular N terminus and an intracellular C terminus. Agonist binding to a β-adrenoceptor induces a change in receptor conformation that permits the receptor to interact with a membrane-bound G protein (Gs and under some conditions Gi). The interaction results in the dissociation of the heterotrimeric G protein into Gα and Gβγ subunits, and either of these modulates
Implications of polymorphisms for cardiovascular disease and therapy
Owing to their central role in cardiovascular homeostasis, numerous clinical studies in ethnically different cohorts have been conducted to assess the relevance of β-adrenoceptor polymorphisms in disease causation, progression and therapy.
Several studies have analyzed the relevance of the Ser49Gly and Gly389Arg β1-adrenoceptor polymorphisms with regard to the promotion of hypertension. Although initial evidence indicated a role for β1-adrenoceptor polymorphisms in blood-pressure regulation, no
Structural insights into β-adrenoceptor activation
Both the sites of interaction between ligands and the β-adrenoceptor and their putative G-protein-coupling regions have been characterized by mutagenesis studies 42, 43, 44, 45, 46. Apart from these analyses that necessarily focused on specific parts of the receptor, our understanding of GPCR structures has, until recently, been based largely on the high-resolution crystal structures of the inactive state and the photoactivated deprotonated state of rhodopsin 47, 48. The structural analysis of
Insights into β-adrenoceptor activation
Several kinetic models have been developed to explain GPCR activation using information derived from indirect measures of receptor conformation, such as changes in ligand-binding affinity and the activation of G proteins or effector enzymes. The first direct evidence for ligand-specific conformational changes occurring in a β-adrenoceptor has been provided by fluorescence spectroscopy assays of the β2-adrenoceptor. To this end, the purified receptors were labelled with conformationally
Impact of polymorphisms on receptor-activation kinetics
Cyan- and yellow-emitting variants of the green fluorescent protein (CFP, or its mutant variant Cerulean, and YFP, respectively) permitted the use of fluorescence resonance energy transfer (FRET) 61, 62 to directly study conformational changes within the β-adrenoceptor. Placement of YFP and CFP in the third intracellular loop and at the C terminus, respectively, enabled the generation of a β1-adrenoceptor construct that allowed the monitoring of receptor conformational changes in real time and
Conclusion
Taken together, both the recent FRET-based analyses of receptor conformation and several clinical studies point towards a functional importance of the polymorphic sites with respect to the therapeutic efficacy of different β-blockers. Real-time receptor-activation analysis in combination with structural data and clinical studies in large, well-characterized patient collectives might aid the choice from existing therapeutics for individualized, more effective pharmacological treatment in
Acknowledgements
We thank Hermann Schindelin, University of Wuerzburg, for helpful discussions of receptor structural data.
References (66)
Subtype-specific α1- and β-adrenoceptor signaling in the heart
Trends Pharmacol. Sci.
(2006)Common polymorphisms of β1-adrenoceptor: identification and rapid screening assay
Lancet
(1999)Characterization of a unique genetic variant in the β1-adrenoceptor gene and evaluation of its role in idiopathic dilated cardiomyopathy. CARDIGENE Group
J. Mol. Cell. Cardiol.
(1999)A gain-of-function polymorphism in a G-protein coupling domain of the human β1-adrenergic receptor
J. Biol. Chem.
(1999)The myocardium-protective Gly-49 variant of the β1-adrenergic receptor exhibits constitutive activity and increased desensitization and down-regulation
J. Biol. Chem.
(2002)Hierarchy of polymorphic variation and desensitization permutations relative to β1- and β2-adrenergic receptor signaling
J. Biol. Chem.
(2003)A polymorphism of the human β2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor
J. Biol. Chem.
(1993)Arg389Gly polymorphism of the human β1-adrenergic receptor in patients with nonfatal acute myocardial infarction
Am. Heart J.
(2003)The Arg389Gly β1-adrenoceptor polymorphism and catecholamine effects on plasma-renin activity
J. Am. Coll. Cardiol.
(2005)β1- and β2-adrenoceptor polymorphisms: functional importance, impact on cardiovascular diseases and drug responses
Pharmacol. Ther.
(2008)
The forgotten serine. A critical role for Ser-2035.42 in ligand binding to and activation of the β2-adrenergic receptor
J. Biol. Chem.
Identification of two serine residues involved in agonist activation of the β-adrenergic receptor
J. Biol. Chem.
G protein-coupled receptors. II. Mechanism of agonist activation
J. Biol. Chem.
GRKs and β-arrestins: roles in receptor silencing, trafficking and signaling
Trends Endocrinol. Metab.
Fluorescent labeling of purified β2-adrenergic receptor. Evidence for ligand-specific conformational changes
J. Biol. Chem.
Agonist-induced conformational changes at the cytoplasmic side of transmembrane segment 6 in the β2-adrenergic receptor mapped by site-selective fluorescent labeling
J. Biol. Chem.
Functionally different agonists induce distinct conformations in the G protein coupling domain of the β2-adrenergic receptor
J. Biol. Chem.
Sequential binding of agonists to the β2-adrenoceptor. Kinetic evidence for intermediate conformational states
J. Biol. Chem.
Probing the β2-adrenoceptor binding site with catechol reveals differences in binding and activation by agonists and partial agonists
J. Biol. Chem.
Adrenergic and muscarinic receptors in the human heart
Pharmacol. Rev.
What is the role of β-adrenergic signaling in heart failure?
Circ. Res.
A novel polymorphism in the gene coding for the β1-adrenergic receptor associated with survival in patients with heart failure
Eur. Heart J.
Amino acid 49 polymorphisms of the human β1-adrenergic receptor affect agonist-promoted trafficking
J. Cardiovasc. Pharmacol.
Markedly reduced effects of (−)-isoprenaline but not of (−)-CGP12177 and unchanged affinity of β-blockers at Gly389- β1-adrenoceptors compared to Arg389- β1-adrenoceptors
Br. J. Pharmacol.
Pharmacology and physiology of human adrenergic receptor polymorphisms
Annu. Rev. Pharmacol. Toxicol.
Autonomic nervous system pharmacogenomics: a progress report
Pharmacol. Rev.
β-adrenoceptor polymorphisms
Naunyn Schmiedebergs Arch. Pharmacol.
β2-adrenoceptor gene polymorphisms
Pharmacogenet. Genomics
Myocardial signaling defects and impaired cardiac function of a human β2-adrenergic receptor polymorphism expressed in transgenic mice
Proc. Natl. Acad. Sci. U. S. A.
Amino-terminal polymorphisms of the human β2-adrenergic receptor impart distinct agonist-promoted regulatory properties
Biochemistry
The CAREGENE study: polymorphisms of the β1-adrenoceptor gene and aerobic power in coronary artery disease
Eur. Heart J.
Variability within α- and β-adrenoreceptor genes as a predictor of cardiovascular function at rest and in response to mental challenge
J. Hypertens.
Genetic polymorphisms of the β-adrenergic system: association with essential hypertension and response to β-blockade
Pharmacogenomics J.
Cited by (10)
Association of polymorphisms in the beta-2 adrenergic receptor gene with fracture risk and bone mineral density
2015, Osteoporosis InternationalClinical implications of recent insights into the structural biology of beta2 adrenoceptors
2012, Current Drug Targets