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

J Biol Chem. 1992 Jan 25;267(3):1430-3.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenergic beta-Agonists / metabolism
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Binding, Competitive
  • Cell Line
  • Cell Membrane / metabolism
  • DNA / genetics
  • Epinephrine / metabolism
  • Epinephrine / pharmacology
  • Inositol Phosphates / metabolism
  • Kinetics
  • Models, Structural
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed*
  • Phenethylamines / metabolism
  • Protein Conformation
  • Receptors, Adrenergic, beta / genetics
  • Receptors, Adrenergic, beta / metabolism*
  • Tetralones*
  • Transfection


  • Adrenergic beta-Agonists
  • Inositol Phosphates
  • Phenethylamines
  • Receptors, Adrenergic, beta
  • Tetralones
  • DNA
  • 2-(beta-(3-iodo-4-hydroxyphenyl)ethylaminomethyl)tetralone
  • Epinephrine