Elsevier

Cellular Signalling

Volume 17, Issue 8, August 2005, Pages 917-928
Cellular Signalling

Review
Pathophysiological roles of G-protein-coupled receptor kinases

https://doi.org/10.1016/j.cellsig.2005.01.002Get rights and content

Abstract

G-protein-coupled receptor kinases (GRKs) interact with the agonist-activated form of G-protein-coupled receptors (GPCRs) to effect receptor phosphorylation and to initiate profound impairment of receptor signalling, or desensitization. GPCRs form the largest family of cell surface receptors known and defects in GRK function have the potential consequence to affect GPCR-stimulated biological responses in many pathological situations. This review focuses on the physiological role of GRKs revealed by genetically modified animals but also develops the involvement of GRKs in human diseases as, Oguchi disease, heart failure, hypertension or rhumatoid arthritis. Furthermore, the regulation of GRK levels in opiate addiction, cancers, psychiatric diseases, cystic fibrosis and cardiac diseases is discussed. Both transgenic mice and human pathologies have demonstrated the importance of GRKs in the signalling pathways of rhodopsin, β-adrenergic and dopamine-1 receptors. The modulation of GRK activity in animal models of cardiac diseases can be effective to restore cardiac function in heart failure and opens a novel therapeutic strategy in diseases with GPCR dysregulation.

Introduction

G-protein-coupled receptors (GPCRs) represent the most diverse group of proteins involved in transmembrane signalling pathways [1]. GPCRs are stimulated by various ligands including neuromediators, glycoproteinic hormones, peptides, biogenic amines, nucleotides, lipids, calcium ions and sensory substances (taste, odor and light). Upon ligand binding (first messenger), conformational changes of the receptor arise and modulate the activity of effector membrane proteins (adenylyl cyclase, phospholipases C and A2, cGMP phosphodiesterase and some ionic channels) through coupling to heterotrimeric G proteins. Afterwards, variations in intracellular second messenger levels, following directly the activation of effector proteins, induce modifications of the cellular metabolism and biological responses.

In addition to G protein coupling, activation of a GPCR by its agonist initiates a negative feedback process known as desensitization [2]. This process wanes membrane signalling and avoids the potentially harmful effects of an excessive cell stimulation. The molecular events underlying a desensitization mechanism start generally with agonist-induced receptor phosphorylation by a G-protein-coupled receptor kinase (GRK) [3]. The phosphorylated GPCR possesses an increased affinity for a cytosolic protein of the arrestin family. This complex (phosphoryled receptor/arrestin) prevents the further coupling of that receptor to its G protein, reducing over time the capacity of second messenger synthesis. Resensitization is triggered by internalization of an uncoupled receptor to endosomal compartments, allowing dephosphorylation of the receptor by a protein phosphatase and recycling back to the cell surface or degradation (Fig. 1).

Seven mammalian genes encoding GRKs (1 to 7) have been cloned to date [4], [5], [6]. All GRKs (∼60–80 kDa) possess a similar structural organization with a N-terminal domain (∼185 amino acids), a catalytic domain (∼270 amino acids) and a C-terminal domain (∼105 to 230 amino acids). With the exception of GRK1, 4 and 7, which are found almost exclusively in a specific organ, GRK2, 3, 4 and 5 exhibit a more ubiquitous tissue distribution in mammals. Based on sequence and functional similarities, the GRK family has been divided into three subfamilies [7]: (a) the rhodopsin kinase subfamily (GRK1 and 7), (b) the β-adrenergic receptor kinase subfamily (GRK2 and 3) and (c) the GRK4 subfamily (GRK4, 5 and 6). Regulation of GRKs by calcium-binding proteins, phosphorylation, targeting proteins, or by mechanisms governing their localizations and expressions, have been detailed elsewhere [8], [9], [10], [11].

GRKs have a key role in GPCR desensitization and because these receptors are involved in so many vital functions, it seems likely that disorders affecting GRK-mediated regulation of GPCR would contribute to, if not engender disease. In humans, genetic mutations of GRK1 and GRK4 have been found in patients with Oguchi disease [12] and hypertension [13], respectively. Furthermore, some studies have shown the fundamental role of GRK2 in cardiac development [14] and function [15]. This article reviews the physiological role of GRKs in light of recent results from genetically modified animals but also develops the involvement and regulation of GRKs in human diseases including cardiac diseases, opiate addiction, cancers, depression, rheumatoid arthritis and cystic fibrosis.

Section snippets

Methodological considerations

Most work attempting to define the specificity of GRK action on individual GPCRs has used in vitro models [16], cultured cells [17] or transgenic mice [18]. These techniques concern a direct phosphorylation of receptors by a GRK with [γ-32P] ATP (in vitro) and gene overexpression (in cultured cells or transgenic mice), using full-size GRK, GRK fragments or kinase-deficient mutants to assess inhibition of individual GRKs. Although, gene overexpression in cultured cells studies the feasibility of

GRK1 and Oguchi disease: retinal degeneration

Mutations associated with retinal degeneration, in Oguchi disease, were reported in the genes encoding GRK1 and visual arrestin [72]. Oguchi disease is an autosomal recessive form of retinitis pigmentosa, with night blindness, characterized by prolonged dark adaptation, abnormal sensitivity to light and golden-brown discoloration of the fundus upon light adaptation. Excessive light exposition induces retinal degeneration, as demonstrated in arrestin and GRK1 knockout mouse models [28], [73],

Regulation of GRK levels in human pathologies

In this chapter, changes in GRK expressions are presented in different human pathologies (Table 2). However, the functional significance of these changes in most of pathologies remains to be established and complementary studies are necessary to clarify these results.

Conclusion and perspectives

Our understanding of the mechanisms involved in the regulation of GPCR desensitization has developed considerably over the past decade. Receptor phosphorylation by GRKs is one of the first steps in this process and therefore plays a key role in the funtional uncoupling of the G proteins from the receptors. It is estimated that at least 1000 different GPCRs are encoded by the human genome and only seven GRKs have been identified in the human kinome [133]. Thus, several GPCRs are targeted by the

Acknowledgements

This work was supported in part by a grant from la Ligue contre le Cancer, Comité de la Vienne. We are grateful to Prof. CJ Larsen and Prof. D Sarrouilhe for their valuable discussions and careful reading of the manuscript.

References (134)

  • J. Wess

    Pharmacol. Ther.

    (1998)
  • P. Penela et al.

    Cell. Signal.

    (2003)
  • R.B. Penn et al.

    Trends Cardiovasc. Med.

    (2000)
  • J. Wess

    Trends Pharmacol. Sci.

    (2000)
  • P. Kunapuli et al.

    J. Biol. Chem.

    (1994)
  • R.R. Gainetdinov et al.

    Neuron

    (1999)
  • H. Kuhn et al.

    FEBS Lett.

    (1972)
  • A. Sitaramayya et al.

    J. Biol. Chem.

    (1983)
  • K. Palczewski et al.

    J. Biol. Chem.

    (1988)
  • H. Ohguro et al.

    J. Biol. Chem.

    (1995)
  • H.A. Rockman et al.

    J. Biol. Chem.

    (1998)
  • D. Diviani et al.

    J. Biol. Chem.

    (1996)
  • G. Parruti et al.

    Biochem. Biophys. Res. Commun.

    (1993)
  • K. Peppel et al.

    J. Biol. Chem.

    (1997)
  • K. Ishii et al.

    J. Biol. Chem.

    (1994)
  • N.J. Freedman et al.

    J. Biol. Chem.

    (1995)
  • M. Oppermann et al.

    J. Biol. Chem.

    (1996)
  • R.T. Premont et al.

    J. Biol. Chem.

    (1996)
  • M. Sallese et al.

    J. Biol. Chem.

    (1997)
  • M. Sallese et al.

    Biochem. Biophys. Res. Commun.

    (1994)
  • L. Iacovelli et al.

    J. Biol. Chem.

    (2003)
  • H. Watanabe et al.

    Kidney Int.

    (2002)
  • M. Tiberi et al.

    J. Biol. Chem.

    (1996)
  • E. Reiter et al.

    Biochem. Biophys. Res. Commun.

    (2001)
  • J.M. Willets et al.

    J. Biol. Chem.

    (2002)
  • N. Aiyar et al.

    Eur. J. Pharmacol.

    (2000)
  • R.R. Gainetdinov et al.

    Neuron

    (2003)
  • D.B. Farber et al.

    Curr. Opin. Neurobiol.

    (1997)
  • S. Arber et al.

    Cell

    (1997)
  • P.A. Jose et al.

    Pharmacol. Ther.

    (1998)
  • R.D. Feldman et al.

    Trends Cardiovasc. Med.

    (1998)
  • W.P. Hausdorff et al.

    FASEB J.

    (1990)
  • J.G. Krupnick et al.

    Annu. Rev. Pharmacol. Toxicol.

    (1998)
  • E.R. Weiss et al.

    Mol. Vis.

    (1998)
  • J.A. Pitcher et al.

    Annu. Rev. Biochem.

    (1998)
  • K. Palczewski

    Eur. J. Biochem.

    (1997)
  • R.T. Premont et al.

    FASEB J.

    (1995)
  • T.A. Kohout et al.

    Mol. Pharmacol.

    (2003)
  • L. Iacovelli et al.

    FASEB J.

    (1999)
  • S. Yamamoto et al.

    Nat. Genet.

    (1997)
  • R.A. Felder et al.

    Proc. Natl. Acad. Sci. U. S. A.

    (2002)
  • M. Jaber et al.

    Proc. Natl. Acad. Sci. U. S. A.

    (1996)
  • M. Ungerer et al.

    Circulation

    (1993)
  • G. Pei et al.

    Proc. Natl. Acad. Sci. U. S. A.

    (1994)
  • A.B. Tobin

    Methods Mol. Biol.

    (1997)
  • M. Shih et al.

    Proc. Natl. Acad. Sci. U. S. A.

    (1994)
  • R.L. Somers et al.

    Science

    (1984)
  • J. Chen et al.

    Science

    (1995)
  • C.K. Chen et al.

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • A.L. Lyubarsky et al.

    J. Neurosci.

    (2000)
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