Protein kinases that phosphorylate activated G protein‐coupled receptors

  title={Protein kinases that phosphorylate activated G protein‐coupled receptors},
  author={R T Premont and James Inglese and R J Lefkowitz},
  journal={The FASEB Journal},
  pages={175 - 182}
G protein‐coupled receptor kinases (GRKs) are a family of serine/threonine protein kinases that specifically recognize agonist‐occupied, activated G protein‐coupled receptor proteins as substrates. Phosphorylation of an activated receptor by a GRK terminates signaling by that receptor, by initiating the uncoupling of the receptor from heterotrimeric G proteins. Six distinct mammalian GRKs are known, which differ in tissue distribution and in regulatory properties. The intracellular localization… 
GTP-binding-protein-coupled receptor kinases--two mechanistic models.
Mechanistic aspects of GPCR* phosphorylation related to the distinct properties, regulation and modes of action of GRKs are described.
Regulation of the G Protein-coupled Receptor Kinase GRK5 by Protein Kinase C*
The results suggest that PKC might play an important role in modulating the ability of GRK5 to regulate receptor signaling and that GRK phosphorylation by PKC may serve as a disparate mechanism for regulating GRK activity.
G-protein-coupled receptor regulation: role of G-protein-coupled receptor kinases and arrestins
GRK-mediated phosphorylation and arrestin binding are not only involved in the functional uncoupling of GPCRs but they are also intimately involved in promoting GPCR sequestration and as such likely play an important role in mediating the subsequent resensitization of G PCRs.
G protein-coupled receptor kinases.
This review focuses on the regulation of GRK activity by a variety of allosteric and other factors: agonist-stimulated GPCRs, beta gamma subunits of heterotrimeric GTP- binding proteins, phospholipid cofactors, the calcium-binding proteins calmodulin and recoverin, posttranslational isoprenylation and palmitoylation, autophosphorylation, and protein kinase C-mediated GRK phosphorylation.
G Protein-Coupled Receptor Kinases
This work focused on retinal GRKs, or photopigment kinases, rhodopsin kinase (GRK1), and GRK7, in the context of major general advances in the GRK fi eld, and decoding of the molecular basis of GRK activation and interactions with GPCR substrates, as well as theGRK interactions with cellular membranes and inhibitors.
G‐protein coupled receptor kinases as modulators of G‐protein signalling
The roles of regulatory molecules as modulators of GPCR signalling are discussed, including members of the arrestin family, which bind to the phosphorylated and activated GPCRs and cause desensitization by precluding further interactions of the G PCRs and G‐proteins.
G-protein-coupled receptor kinases.
A pathophysiological role for GRKs can be inferred from recent studies on heart failure as well as the observation that chronic treatment with various agonists or antagonists for G-protein-coupled receptors results in alterations of GRK expression.
Receptor and G betagamma isoform-specific interactions with G protein-coupled receptor kinases.
This study provides a direct demonstration of a role for G betagamma in mediating the agonist-stimulated translocation of GRK2 and GRK3 in an intact cellular system and demonstrates isoform specificity in the interaction of these components.
Regulation of G Protein-coupled Receptor Kinases by Calmodulin and Localization of the Calmodulin Binding Domain*
It is demonstrated that calmodulin, another mediator of calcium signaling, is a potent inhibitor of GRK activity with a selectivity for GRK5 (IC50 ∼50 nm) > GRK6 ≫ GRK2 ( IC50 ∼2 μm) ≬ GRK1.
Structure-Function Analysis of G Protein-coupled Receptor Kinase-5
It is demonstrated that the C-terminal region of GRK5 (residues 563–590) contains residues autophosphorylated in the presence of calmodulin as well as the residues phosphorylated by protein kinase C, defined as an autoinhibitory domain with efficacy that is regulated by phosphorylation.


Structure and mechanism of the G protein-coupled receptor kinases.
It has been proposed that the designation GRK be adopted with numbering pro-ceeding in the chronological order of the kinase’s (4) GRKs, for members of this kinase gene family for which the functional roles remain completely unknown.
Phospholipid-stimulated autophosphorylation activates the G protein-coupled receptor kinase GRK5.
Results suggest that phospholipid-stimulated autophosphorylation may represent a novel mechanism for membrane association and regulation of GRK5 activity.
Isoprenylation in regulation of signal transduction by G-protein-coupled receptor kinases
The results indicate that rhodopsin kinase and β ARK both rely on the function of isoprenyl moieties for their translocation and activity, illustrating distinct, though related, modes of biological regulation of receptor function.
Cloning and expression of GRK5: a member of the G protein-coupled receptor kinase family.
  • P. Kunapuli, J. Benovic
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1993
The isolation of a cDNA that encodes a 590-amino acid protein kinase, termed GRK5, which was able to phosphorylate rhodopsin in a light-dependent manner and represents a member of the GRK family that likely has a unique physiological role.
Isolation of Drosophila genes encoding G protein-coupled receptor kinases.
The isolation of a family of genes encoding a set of Drosophila protein kinases that appear to code for G protein-coupled receptor kinases is reported, pointing to the central role of these kinases in signal transduction cascades.
An approach to the study of G-protein-coupled receptor kinases: an in vitro-purified membrane assay reveals differential receptor specificity and regulation by G beta gamma subunits.
An approach is described that obviates this problem by utilizing highly purified membrane preparations from Sf9 and 293 cells overexpressing G-protein-coupled receptors to demonstrate specificity of several GRKs with respect to both receptor substrates and the enhancing effects of G- protein beta gamma subunits on phosphorylation.