Constitutively active mutants of the alpha 2-adrenergic receptor.

Détails

ID Serval
serval:BIB_90B1A4AFB5E6
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Constitutively active mutants of the alpha 2-adrenergic receptor.
Périodique
Journal of Biological Chemistry
Auteur(s)
Ren Q., Kurose H., Lefkowitz R.J., Cotecchia S.
ISSN
0021-9258 (Print)
ISSN-L
0021-9258
Statut éditorial
Publié
Date de publication
1993
Peer-reviewed
Oui
Volume
268
Numéro
22
Pages
16483-16487
Langue
anglais
Résumé
We have mutated a single residue, Thr373 [corrected], in the C-terminal portion of the third intracellular loop of the alpha 2C10-adrenergic receptor into five different amino acids. In analogy with the effect of similar mutations in the alpha 1B- and beta 2-adrenergic receptors, these substitutions resulted in two major biochemical modifications: 1) increased constitutive activity of the alpha 2-adrenergic receptor leading to agonist-independent inhibition of adenylyl cyclase and 2) increased affinity of the receptor for binding agonist but not antagonists. The increased constitutive activity of the mutated alpha 2-adrenergic receptors could be inhibited by pertussis toxin, clearly indicating that it results from spontaneous ligand-independent receptor coupling to Gi. In contrast, the increased affinity of the mutant receptors for binding agonists was unaffected by pertussis toxin treatment, indicating that this is an inherent property of the receptors not dependent on interaction with Gi. Coexpression of the receptor mutants with the receptor-specific kinase, beta ARK1, indicated that the constitutively active alpha 2-adrenergic receptors are substrates for beta-adrenergic receptor kinase (beta ARK)-mediated phosphorylation even in the absence of agonist. These findings strengthen the idea that constitutively active adrenergic receptors mimic the "active" state of a G protein-coupled receptor adopting conformations similar to those induced by agonist when it binds to wild type receptors. In addition, these results extend the notion that in the adrenergic receptor family the C-terminal portion of the third intracellular loop plays a general role in the processes involved in receptor activation.
Mots-clé
Adenylate Cyclase/antagonists & inhibitors, Adenylate Cyclase Toxin, Animals, Binding, Competitive, Cell Line, Cyclic AMP-Dependent Protein Kinases, GTP-Binding Proteins/metabolism, Mutation, Pertussis Toxin, Phosphorylation, Polymerase Chain Reaction, Protein Kinases/metabolism, Receptors, Adrenergic, alpha/genetics, Receptors, Adrenergic, alpha/metabolism, Virulence Factors, Bordetella/pharmacology, beta-Adrenergic Receptor Kinases
Pubmed
Web of science
Création de la notice
24/01/2008 12:05
Dernière modification de la notice
03/03/2018 19:26
Données d'usage