GTP-binding-protein-coupled receptor kinases--two mechanistic models

Eur J Biochem. 1997 Sep 1;248(2):261-9. doi: 10.1111/j.1432-1033.1997.00261.x.


Six vertebrate protein kinases (G-protein-coupled receptor kinases; GRKs) that regulate the function of G-protein-coupled receptors (GPCRs) were recently cloned; several distinct properties set them apart from conventional second-messenger regulated protein kinases. It appears that GRKs bind GPCR* through two separate sites: a high-affinity site, which involves intracellular loops of the activated receptor, and the lower-affinity site, encompassing the phosphorylation region. The high-affinity interaction may involve complementary structural elements of GRKs and GPCRs* rather than precise amino acid alignment, thus allowing broad and overlapping specificities of these kinases, in spite of differences in the sequences of GPCRs. In addition, GRK structures are modified by several posttranslational modifications, including phosphorylation, autophosphorylation, prenylation, carboxymethylation, and palmitoylation, probably affecting properties of these enzymes. While GRKs phosphorylate and inactivate receptor molecules which are engaged in G-protein activation, controversy surrounds whether GRKs might be activated and phosphorylate unstimulated GPCRs, leading to a desensitization of a larger population of the receptors. In this review, mechanistic aspects of GPCR* phosphorylation related to the distinct properties, regulation and modes of action of GRKs are described.

Publication types

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

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • G-Protein-Coupled Receptor Kinase 3
  • G-Protein-Coupled Receptor Kinase 4
  • G-Protein-Coupled Receptor Kinase 5
  • G-Protein-Coupled Receptor Kinases
  • GTP-Binding Proteins / metabolism*
  • Humans
  • Lipid Metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases*
  • Receptor Protein-Tyrosine Kinases / chemistry
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptors, Cell Surface / metabolism
  • Substrate Specificity
  • beta-Adrenergic Receptor Kinases


  • Receptors, Cell Surface
  • Receptor Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • G-Protein-Coupled Receptor Kinase 3
  • GRK3 protein, human
  • beta-Adrenergic Receptor Kinases
  • G-Protein-Coupled Receptor Kinase 4
  • G-Protein-Coupled Receptor Kinase 5
  • G-Protein-Coupled Receptor Kinases
  • G-protein-coupled receptor kinase 6
  • GRK4 protein, human
  • GRK5 protein, human
  • GTP-Binding Proteins
  • Calcium