title: A polymorphism of G-protein coupled receptor kinase5 alters agonist-promoted desensitization of beta2-adrenergic receptors.
abstract: Beta-agonist treatment of asthma displays substantial interindividual variation, which has prompted polymorphism discovery and characterization of beta2-adrenergic (beta2AR) signaling genes. beta2AR function undergoes desensitization during persistent agonist exposure because of receptor phosphorylation by G-protein coupled receptor kinases (GRKs). GRK5 was found to be highly expressed in airway smooth muscle, the tissue target for beta-agonists. The coding region is polymorphic at codon 41, where Gln can be substituted by Leu (minor allele), but almost exclusively in those of African descent. In transfected cells, GRK5-Leu41 evoked a greater degree of agonist-promoted desensitization of adenylyl cyclase compared with GRK5-Gln41. Consistent with this functional effect, agonist-promoted beta2AR phosphorylation was greater in cells expressing GRK5-Leu41, as was the rate of agonist-promoted receptor internalization. In studies with mutated beta2AR lacking PKA-phosphorylation sites, this phenotype was confirmed as being GRK-specific. So, GRK5-Leu41 represents a gain-of-function polymorphism that evokes enhanced loss-of-function of beta2AR during persistent agonist exposure, and thus may contribute to beta-agonist variability in asthma treatment of African-Americans.
authors.affiliation: Cardiopulmonary Genomics Program, Department of Medicine, University of Maryland, Baltimore, MD 21201-1075 USA.
authors.forename: Wayne C H
authors.initials: WC
authors.lastname: Wang
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Mihlbachler
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Bleecker
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Liggett
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists; D000818:Animals; D002460:Cell Line; D004705:Endocytosis / Q000187:drug effects; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D018343:Receptors, Adrenergic, beta-2; D054774:G-Protein-Coupled Receptor Kinase 5; C517898:GRK5 protein, human; D007545:Isoproterenol