Constitutively active alpha-1b adrenergic receptor mutants display different phosphorylation and internalization features.

Détails

ID Serval
serval:BIB_346593FE71EA
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Constitutively active alpha-1b adrenergic receptor mutants display different phosphorylation and internalization features.
Périodique
Molecular Pharmacology
Auteur(s)
Mhaouty-Kodja S., Barak L.S., Scheer A., Abuin L., Diviani D., Caron M.G., Cotecchia S.
ISSN
0026-895X (Print)
ISSN-L
0026-895X
Statut éditorial
Publié
Date de publication
1999
Volume
55
Numéro
2
Pages
339-347
Langue
anglais
Résumé
We compared the phosphorylation and internalization properties of constitutively active alpha-1b adrenergic receptor (AR) mutants carrying mutations in two distant receptor domains, i.e., at A293 in the distal part of the third intracellular loop and at D142 of the DRY motif lying at the end of the third transmembrane domain. For the A293E and A293I mutants the levels of agonist-independent phosphorylation were 150% and 50% higher than those of the wild-type alpha-1b AR, respectively. On the other hand, for the constitutively active D142A and D142T mutants, the basal levels of phosphorylation were similar to those of the wild-type alpha-1b AR and did not appear to be further stimulated by epinephrine. Overexpression of the guanyl nucleotide binding regulatory protein-coupled receptor kinase GRK2 further increases the basal phosphorylation of the A293E mutant, but not that of D142A mutant. Both the wild-type alpha-1b AR and the A293E mutant could undergo beta-arrestin-mediated internalization. The epinephrine-induced internalization of the constitutively active A293E mutant was significantly higher than that of the wild-type alpha-1b AR. In contrast, the D142A mutant was impaired in its ability to interact with beta-arrestin and to undergo agonist-induced internalization. Interestingly, a double mutant A293E/D142A retained very high constitutive activity and regulatory properties of both the A293E and D142A receptors. These findings demonstrate that two constitutively activating mutations occurring in distant receptor domains of the alpha-1b AR have divergent effects on the regulatory properties of the receptor.
Mots-clé
Adrenergic Agonists/pharmacology, Amino Acid Substitution, Animals, Arrestins/genetics, Arrestins/metabolism, COS Cells, Cell Line, Cricetinae, Cyclic AMP-Dependent Protein Kinases/drug effects, Cyclic AMP-Dependent Protein Kinases/genetics, Endocytosis/drug effects, Endocytosis/genetics, Epinephrine/pharmacology, Gene Expression Regulation, Green Fluorescent Proteins, Humans, Luminescent Proteins/genetics, Luminescent Proteins/metabolism, Microscopy, Fluorescence, Mutation, Phosphorylation/drug effects, Receptors, Adrenergic, alpha-1/drug effects, Receptors, Adrenergic, alpha-1/genetics, Recombinant Fusion Proteins/drug effects, Recombinant Fusion Proteins/genetics, beta-Adrenergic Receptor Kinases
Pubmed
Web of science
Création de la notice
24/01/2008 11:05
Dernière modification de la notice
20/08/2019 13:21
Données d'usage