Constitutive activation of the alpha 1B-adrenergic receptor by all amino acid substitutions at a single site. Evidence for a region which constrains receptor activation.

Journal Article

Mutations in an intracellular region of the alpha 1B-adrenergic receptor constitutively activate the receptor, resulting in G protein coupling in the absence of agonist, as evidenced by elevated levels of polyphosphoinositide hydrolysis. Remarkably, all 19 possible amino acid substitutions at a single site in this region (alanine 293) confer constitutive activity. This set of mutated receptors exhibits a graded range of elevated biological activities, apparently representing a spectrum of receptor conformations which mimic the "active" state of the wild type receptor. In addition to their constitutive activities, these mutated receptors all demonstrate a higher affinity for agonists, another primary characteristic of the "active" conformation of G protein-coupled receptors. The fact that all possible mutations at this particular site result in increased activity suggests that this region may function to constrain the G protein coupling of the receptor, a constraint which is normally relieved by agonist occupancy.

Full Text

Duke Authors

Cited Authors

  • Kjelsberg, MA; Cotecchia, S; Ostrowski, J; Caron, MG; Lefkowitz, RJ

Published Date

  • January 25, 1992

Published In

Volume / Issue

  • 267 / 3

Start / End Page

  • 1430 - 1433

PubMed ID

  • 1346134

International Standard Serial Number (ISSN)

  • 0021-9258

Language

  • eng

Conference Location

  • United States