Identification of a receptor/G-protein contact site critical for signaling specificity and G-protein activation

Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11642-6. doi: 10.1073/pnas.92.25.11642.


Each G protein-coupled receptor recognizes only a distinct subset of the many structurally closely related G proteins expressed within a cell. How this selectively is achieved at a molecular level is not well understood, particularly since no specific point-to-point contact sites between a receptor and its cognate G protein(s) have been identified. In this study, we demonstrate that a 4-aa epitope on the m2 muscarinic acetylcholine receptor, a prototypical Gi/o-coupled receptor, can specifically recognize the C-terminal 5 aa of alpha subunits of the Gi/o protein family. The m2 receptor residues involved in this interaction are predicted to be located on one side of an alpha-helical receptor region present at the junction between the third intracellular loop and the sixth transmembrane domain. Coexpression studies with hybrid m2/m3 muscarinic receptors and mutant G-protein alpha q subunits showed that the receptor/G-protein contact site identified in this study is essential for coupling specificity and G-protein activation.

MeSH terms

  • Adenylyl Cyclases / metabolism
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cells, Cultured
  • Enzyme Activation
  • GTP-Binding Proteins / metabolism*
  • Hydrolysis
  • Molecular Sequence Data
  • Phosphatidylinositols / metabolism
  • Protein Binding
  • Receptor, Muscarinic M2
  • Receptor, Muscarinic M3
  • Receptors, Muscarinic / genetics
  • Receptors, Muscarinic / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction*
  • Structure-Activity Relationship
  • Type C Phospholipases / metabolism


  • Phosphatidylinositols
  • Receptor, Muscarinic M2
  • Receptor, Muscarinic M3
  • Receptors, Muscarinic
  • Recombinant Fusion Proteins
  • Type C Phospholipases
  • GTP-Binding Proteins
  • Adenylyl Cyclases