title: Genetic variation of human adrenergic receptors: from molecular and functional properties to clinical and pharmacogenetic implications.
abstract: Adrenergic receptors (ARs) are directly or indirectly involved in the control of a large panel of physiological functions and are the targets of drugs for the treatment of several common diseases including congestive heart failure, asthma or benign prostatic hyperplasia. The genotyping of human populations with diverse ethnicity has revealed that the genes encoding alpha(1A)-, alpha(1B)-, alpha(2A)-, alpha(2B)-, alpha(2C)-, beta(1)-, beta(2)- and beta(3)-AR are polymorphic in their coding region as well as in their regulatory domains and non-coding regions. The functional consequences of these genetic variations include changes in expression at transcriptional or translational level, modification of coupling to heterotrimeric G-proteins resulting in a gain or a loss in function, and alteration of GRK-mediated receptor phosphorylation/desensitization or of agonist-promoted down-regulation. None of the mutations identified so far is per se a major risk factor for acquired or inherited disease; however, variants of alpha(2C)-AR and beta(1)-AR may act in synergy to determine the progression of heart failure and certain combinations of polymorphisms on beta(2)-AR correlate with asthmatic phenotypes or response to beta(2)-agonist therapy. Herein we summarize the present knowledge on AR gene polymorphisms, and discuss the putative consequences of variations resulting in receptor malfunction on pharmacogenomics and disease predisposition.
authors.affiliation: INSERM, U388, Institut Louis Bugnard, CHU Rangueil, Toulouse, France. stephane.schaak@toulouse.inserm.fr
authors.forename: Stéphane
authors.initials: S
authors.lastname: Schaak
authors.forename: Jeanne
authors.initials: J
authors.lastname: Mialet-Perez
authors.forename: Christodoulos
authors.initials: C
authors.lastname: Flordellis
authors.forename: Hervé
authors.initials: H
authors.lastname: Paris
mesh_terms: D018663:Adrenergic Agents / Q000494:pharmacology*; D014644:Genetic Variation; D006801:Humans; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011941:Receptors, Adrenergic / Q000145:classification / Q000235:genetics*
chemical_list: D018663:Adrenergic Agents; D011941:Receptors, Adrenergic