Amino acid 49 polymorphisms of the human beta1-adrenergic receptor affect agonist-promoted trafficking.
The signaling impact of a human beta1-adrenergic receptor (beta1 AR) polymorphism at residue 49 of the aminoterminus (Ser-to-Gly substitution) was studied by recombinantly expressing each receptor. The two receptors displayed identical agonist and antagonist binding affinities. Furthermore, basal and agonist-stimulated adenylyl cyclase activities were the same for these receptors as assessed in both cell types. Although short-term agonist exposure resulted in similar degrees of receptor internalization, long-term agonist-promoted downregulation was greater for Gly49 compared with Ser49. The Gly49 receptor underwent a 24 +/- 3% loss of receptor density after exposure to isoproterenol for 18 h, whereas Ser49 underwent no such loss. In studies in which receptor synthesis was inhibited, agonist-promoted downregulation for Gly49 was 55 +/- 3% compared with 36 +/- 5% for Ser49. In the absence of agonist, degradative turnover of each receptor was the same. Immunoblotting revealed that some of the Ser49 receptor exists as a highly N-glycosylated form (approximately 105-kD molecular mass), which is not present with Gly49. Thus the phenotype of the Gly49 polymorphic receptor is that of wild-type coupling with enhanced agonist-promoted downregulation, which is associated with altered N-glycosylation. Based on this cellular phenotype, the beta1 AR Gly49 polymorphism may impart a beneficial effect in chronic heart failure.
Rathz
Deborah A
DA
Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0564, USA.
Brown
Kari M
KM
Kramer
Lisa A
LA
Liggett
Stephen B
SB
D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D019943:Amino Acid Substitution; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D015536:Down-Regulation; D006801:Humans; D016297:Mutagenesis, Site-Directed; D011110:Polymorphism, Genetic; D021381:Protein Transport; D011869:Radioligand Assay; D018342:Receptors, Adrenergic, beta-1 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D018342:Receptors, Adrenergic, beta-1; D011994:Recombinant Proteins; D000262:Adenylyl Cyclases