G protein‐coupled receptor kinase 2 (GRK2): mechanisms of regulation and physiological functions

Abstract

G protein-coupled receptor kinase 2 (GRK2) plays a key role in determining the rate and extent of G protein-coupled receptor (GPCR) desensitization and resensitization. Recent data indicate that GRK2 activity, subcellular distribution and expression are tightly regulated. The important physiological function of GRK2 as a modulator of the efficacy of GPCR signal transduction systems is exemplified by its relevance in cardiovascular physiopathology as well as by its emerging role in the regulation of chemokine receptors.z 1998 Federation of European Biochemical Societies.Key words: G protein-coupled receptor kinase; Desensitization; Cardiovascular; Chemokine receptorThe cellular responses to agonists acting through G proteincoupled receptors (GPCRs) are usually rapidly attenuated, a process that is critical to prevent the uncontrolled stimulation of cells. Mechanisms of attenuation include removal of agonist from the extracellular £uid and receptor desensitization, endocytosis and down-regulation. Receptor phosphorylation by speci¢c G protein-coupled receptor kinases (GRKs) plays a key role in triggering rapid desensitization [1^5]. The GRKmediated phosphorylation of the agonist-occupied receptor promotes the binding of a member of the family of uncoupling proteins termed L-arrestins, resulting in the uncoupling of the receptor from G proteins.There are six known members of the GRK family, GRK1 to GRK6, which share a number of structural and functional similarities [2,4,6,7] and di¡er in both an N-terminal domain of largely unknown function, and a C-terminal domain of variable length, that contains speci¢c determinants for membrane attachment. GRK2 is a ubiquitous member of the GRK family which has been shown to phosphorylate a variety of GPCRs (see [3] for a recent review). Recent evidence indicates that, besides promoting receptor uncoupling, GRK2 would also directly participate in GPCR sequestration, thus triggering receptor dephosphorylation and recycling [5,8^10]. Moreover, GRK2 and L-arrestin have been suggested to participate in the regulation of the mitogen-activated protein kinase cascade by GPCR [11]. This fact, together with the recently reported phosphorylation of tubulin by GRK2 [12], further stresses the relevance of this kinase in GPCR signaling. This review focuses on the mechanisms of regulation of GRK2 activity and subcellular distribution, as well as on some physiological processes in which an important participation of this kinase has recently been unveiled. Modulation of GRK2 subcellular distribution and activityGRK2 activity and subcellular localization appear to be subject to complex regulatory processes. Although GRK2 was initially described as a soluble, cytosolic enzyme that transiently translocates to the plasma membrane upon receptor activation, recent data indicate that several GRK2 pools exist inside the cells: cytosolic, plasma membrane-bound and microsomal membrane-bound [11,13^15]. Interestingly, GRK2 activity is regulated upon interaction with several proteins and lipids ...

Phosphorylation of Phosducin and Phosducin-like Protein by G Protein-coupled Receptor Kinase 2

“…GRK2 cellular levels, activity, and subcellular localization appear to be tightly controlled through different mechanisms (1,5,11), consistent with the idea that this kinase plays different important roles in cellular signaling. Agonist-induced translocation of GRK2 to the plasma membrane involves its interaction with receptor domains and binding of the C-terminal domain of GRK2 to both free G␤␥ subunits and phosphatidylinositol-4,5-bisphosphate (12,13).…”

“…[1][2][3]. GRK2 is a ubiquitous member of the GRK family, which is able to phosphorylate a variety of GPCR (4,5). Recent data indicate that GRK2 and ␤-arrestins play additional roles in GPCR regulation and signaling.…”

Antidiabetic effect of novel modulating peptides of G-protein-coupled kinase in experimental models of diabetes

“…A strategy for enhancing metabolism-related GPCR signalling is to prevent receptor desensitisation. Gprotein-coupled receptor kinases (GRK) down-regulate signal transduction initiated by GPCRs via phosphorylation of specific sites located on the receptors [11,12,13,14]. Inhibition of GRK-mediated GPCR desensitisation prolongs receptor activation, resulting in increased ligand-induced GPCR activity.…”

Cross-regulation of VPAC2 receptor internalization by m2 receptors via c-Src-mediated phosphorylation of GRK2

“…Phosphorylation of the receptor by GRK2 allows interaction of β-arrestin with receptor and β-arrestin-mediated recruitment of clathrin, thus initiating receptor internalization, as a prelude to deposphorylation and recycling of the receptor. GRK2 activity was shown to be regulated by phosphorylation on serine residues by other kinases such as PKA, PKC ERK1/2 and on tyrosine residue by kinases such as c-Src [16,18,22,27]. Direct phosphorylation of GRK2 on serine 29 located in the calmodulin binding of GRK2 by PKC leads to an increase in GRK2 activity by eliminating the inhibition exerted by the binding of calmodulin, whereas phosphorylation of Raf-kinase inhibitor protein (RKIP) by PKC and subsequent switching of RKIP binding from its known target, Raf-1 to GRK2, leads to inhibition of GRK2 activity [24,31].…”

“…Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Most studies on receptor regulation have used GRK2 as a prototype kinase that phosphorylates many G protein-coupled receptors [16][17][18]. The activity and localization of GRK2 are regulated by phosphorylation by kinases such as PKA, protein kinase C (PKC), c-Src, and extracellular regulated kinases (ERK1/2) and binding to signaling molecules such as phosphatidylinositol 4,5-bisphosphate, calmodulin, caveolin, and Gβ γ subunits [14,16,[18][19][20][21][22][23][24][25][26][27].…”