Negative antagonists promote an inactive conformation of the beta 2-adrenergic receptor.

Details

Serval ID
serval:BIB_981608AB1E1D
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Negative antagonists promote an inactive conformation of the beta 2-adrenergic receptor.
Journal
Molecular Pharmacology
Author(s)
Samama P., Pei G., Costa T., Cotecchia S., Lefkowitz R.J.
ISSN
0026-895X (Print)
ISSN-L
0026-895X
Publication state
Published
Issued date
1994
Volume
45
Number
3
Pages
390-394
Language
english
Abstract
The beta 2-adrenergic receptor undergoes isomerization between an inactive conformation (R) and an active conformation (R*). The formation of the active conformation of the receptor molecule can be promoted by adrenergic agonists or by mutations in the third cytoplasmic domain that constitutively activate the receptor. Here we show that, of several beta-adrenergic receptor-blocking drugs tested, only two, ICI 118551 and betaxolol, inhibit the basal signaling activity of the beta 2-adrenergic receptor, thus acting as negative antagonists. We document the molecular properties of the more efficacious ICI 118551; (i) it shows higher affinity for the inactive form of the receptor and (ii) it inhibits the spontaneous formation of a beta-adrenergic receptor kinase substrate by the receptor. These properties are opposite those of adrenergic agonists, indicating that, in a fashion reciprocal to that of agonists, negative antagonists promote the formation of an inactive conformation of the receptor.
Keywords
Adrenergic beta-Antagonists/pharmacology, Allosteric Site, Animals, Baculoviridae/genetics, Betaxolol/pharmacology, Binding Sites, CHO Cells, Cricetinae, Lepidoptera, Phosphorylation, Propanolamines/pharmacology, Protein Conformation, Receptors, Adrenergic, beta/chemistry, Receptors, Adrenergic, beta/genetics, Signal Transduction
Pubmed
Web of science
Create date
24/01/2008 11:05
Last modification date
20/08/2019 14:59
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