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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Samama, P; Pei, G; Costa, T; Cotecchia, S; Lefkowitz, RJ

Published Date

  • March 1994

Published In

Volume / Issue

  • 45 / 3

Start / End Page

  • 390 - 394

PubMed ID

  • 7908404

Pubmed Central ID

  • 7908404

Electronic International Standard Serial Number (EISSN)

  • 1521-0111

International Standard Serial Number (ISSN)

  • 0026-895X

Language

  • eng