Structure-function relationships of the alpha1b-adrenergic receptor.

Détails

ID Serval
serval:BIB_0283E3385720
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Structure-function relationships of the alpha1b-adrenergic receptor.
Périodique
European Urology
Auteur(s)
Scheer A., Fanelli F., Diviani D., de Benedetti P.G., Cotecchia S.
ISSN
0302-2838 (Print)
ISSN-L
0302-2838
Statut éditorial
Publié
Date de publication
1999
Volume
36 Suppl 1
Pages
11-16
Langue
anglais
Résumé
The alpha1b-adrenergic receptor (AR) is a member of the large superfamily of seven transmembrane domain (TMD) G protein-coupled receptors (GPCR). Combining site-directed mutagenesis of the alpha1b-AR with computational simulations of receptor dynamics, we have explored the conformational changes underlying the process of receptor activation, i.e. the transition between the inactive and active states. Our findings suggest that the structural constraint stabilizing the alpha1b-AR in the inactive form is a network of H-bonding interactions amongst conserved residues forming a polar pocket and R143 of the DRY sequence at the end of TMDIII. We have recently reported that point mutations of D142, of the DRY sequence and of A293 in the distal portion of the third intracellular loop resulted in ligand-independent (constitutive) activation of the alpha1b-AR. These constitutively activating mutations could induce perturbations resulting in the shift of R143 out of the polar pocket. The main role of R143 may be to mediate receptor activation by triggering the exposure of several basic amino acids of the intracellular loops towards the G protein. Our investigation has been extended also to the biochemical events involved in the desensitization process of alpha1b-AR. Our results indicate that immediately following agonist-induced activation, the alpha1b-AR can undergo rapid agonist-induced phosphorylation and desensitization. Different members of the G protein coupled receptor kinase family can play a role in agonist-induced regulation of the alpha1b-AR. In addition, constitutively active alpha1b-AR mutants display different phosphorylation and internalization features. The future goal is to further elucidate the molecular mechanism underlying the complex equilibrium between activation and inactivation of the alpha1b-AR and its regulation by pharmacological substances. These findings can help to elucidate the mechanism of action of various agents displaying properties of agonists or inverse agonists at the adrenergic system.
Mots-clé
Adrenergic beta-Agonists/pharmacology, GTP-Binding Proteins/metabolism, Humans, Phosphorylation, Point Mutation, Receptors, Adrenergic, beta-1/chemistry, Receptors, Adrenergic, beta-1/genetics, Structure-Activity Relationship
Pubmed
Web of science
Création de la notice
24/01/2008 11:05
Dernière modification de la notice
20/08/2019 12:24
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