Regulation of G protein-coupled receptor kinase subtypes by calcium sensor proteins

Biochim Biophys Acta. 2000 Dec 20;1498(2-3):112-21. doi: 10.1016/s0167-4889(00)00088-4.


G protein-coupled receptor homologous desensitization is intrinsically related to the function of a class of S/T kinases named G protein-coupled receptor kinases (GRK). The GRK family is composed of six cloned members, named GRK1 to 6. Studies from different laboratories have demonstrated that different calcium sensor proteins (CSP) can selectively regulate the activity of GRK subtypes. In the presence of calcium, rhodopsin kinase (GRK1) is inhibited by the photoreceptor-specific CSP recoverin through direct binding. Several other recoverin homologues (including NCS 1, VILIP 1 and hippocalcin) are also able to inhibit GRK1. The ubiquitous calcium-binding protein calmodulin (CaM) can inhibit GRK5 with a high affinity (IC(50)=40-50 nM). A direct interaction between GRK5 and Ca(2+)/CaM was documented and this binding does not influence the catalytic activity of the kinase, but rather reduced GRK5 binding to the membrane. These studies suggest that CSP act as functional analogues in mediating the regulation of different GRK subtypes by Ca(2+). This mechanism is, however, highly selective with respect to the GRK subtypes: while GRK1, but not GRK2 and GRK5, is regulated by recoverin and other NCS, GRK4, 5 and 6, that belong to the GRK4 subfamily, are potently inhibited by CaM, which had little or no effect on members of other GRK subfamilies.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Arrestin / genetics
  • Calcium / metabolism
  • Calcium Signaling*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Calcium-Binding Proteins / pharmacology
  • Calmodulin / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • EF Hand Motifs
  • Eye Proteins*
  • G-Protein-Coupled Receptor Kinase 1
  • G-Protein-Coupled Receptor Kinase 4
  • G-Protein-Coupled Receptor Kinase 5
  • Hippocalcin
  • Humans
  • Lipoproteins*
  • Nerve Tissue Proteins*
  • Neuronal Calcium-Sensor Proteins
  • Neuropeptides / pharmacology
  • Protein Binding
  • Protein Kinase Inhibitors
  • Protein Kinases / genetics
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Recoverin
  • beta-Adrenergic Receptor Kinases


  • Arrestin
  • Calcium-Binding Proteins
  • Calmodulin
  • Eye Proteins
  • HPCA protein, human
  • Lipoproteins
  • Nerve Tissue Proteins
  • Neuronal Calcium-Sensor Proteins
  • Neuropeptides
  • Protein Kinase Inhibitors
  • RCVRN protein, human
  • frequenin calcium sensor proteins
  • Recoverin
  • Hippocalcin
  • Protein Kinases
  • Protein-Serine-Threonine Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • G-Protein-Coupled Receptor Kinase 1
  • GRK1 protein, human
  • beta-Adrenergic Receptor Kinases
  • G-Protein-Coupled Receptor Kinase 4
  • G-Protein-Coupled Receptor Kinase 5
  • GRK4 protein, human
  • GRK5 protein, human
  • Calcium

Grant support