Multisite contacts involved in coupling of the beta-adrenergic receptor with the stimulatory guanine-nucleotide-binding regulatory protein. Structural and functional studies by beta-receptor-site-specific synthetic peptides

Eur J Biochem. 1991 Jun 1;198(2):357-64. doi: 10.1111/j.1432-1033.1991.tb16023.x.


Synthetic peptides, 12-22 amino acid residues long, comprising the presumed coupling sites of the beta-adrenergic receptor with the stimulatory guanine-nucleotide-binding regulatory protein (Gs), were examined for their ability to modulate Gs activation in turkey erythrocyte membranes. Three peptides corresponding to the second cytoplasmic loop, the N-terminal region of the third cytoplasmic loop, and the N-terminal region of the putative fourth cytoplasmic loop, compete synergistically with the hormone-stimulated receptor for Gs activation with median effector concentrations of 15-35 microM, or 3-4 microM for combinations of two peptides. One peptide, corresponding to the C-terminal region of the third cytoplasmic loop, carries the unique ability to activate the Gs-adenylate-cyclase complex independent of the signalling state of the receptor. These observations are consistent with a dynamic model of receptor-mediated G-protein activation in membranes, where domains composed of the second, third and fourth intracellular loop of the receptor bind to and are interactive with the G-protein heterotrimer, resulting in ligand-induced conformational changes of the receptor. In response to hormone binding, the extent or the number of sites involved in interaction with Gs may be readjusted using a fourth site. Modulation of coupling sites may elicit congruent conformational changes within the Gs heterotrimer, with qualitatively different effects on GTP/GDP exchange in the alpha subunit of Gs and downstream effector regulation. This model corroborates and expands a similar model suggested for activated rhodopsin-transducin interaction [König, B., Arendt, A., McDowell, J. H., Kahlert, M., Hargrave, P. A. & Hofmann, K. P. (1989) Proc. Natl Acad. Sci. USA 86, 6878-6882].

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aluminum / pharmacology
  • Aluminum Compounds*
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Binding, Competitive
  • Dihydroalprenolol / blood
  • Erythrocyte Membrane / metabolism*
  • Fluorides*
  • Fluorine / pharmacology
  • GTP-Binding Proteins / blood*
  • Guanosine 5'-O-(3-Thiotriphosphate) / pharmacology
  • Kinetics
  • Models, Molecular
  • Molecular Sequence Data
  • Oligopeptides / chemical synthesis
  • Oligopeptides / pharmacology
  • Peptides / chemical synthesis
  • Peptides / pharmacology*
  • Protein Conformation
  • Receptors, Adrenergic, beta / drug effects
  • Receptors, Adrenergic, beta / metabolism*
  • Turkeys


  • Aluminum Compounds
  • Oligopeptides
  • Peptides
  • Receptors, Adrenergic, beta
  • tetrafluoroaluminate
  • Fluorine
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Dihydroalprenolol
  • Aluminum
  • GTP-Binding Proteins
  • Fluorides