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Multiple functions of G protein-coupled receptor kinases

Abstract

Desensitization is a physiological feedback mechanism that blocks detrimental effects of persistent stimulation. G protein-coupled receptor kinase 2 (GRK2) was originally identified as the kinase that mediates G protein-coupled receptor (GPCR) desensitization. Subsequent studies revealed that GRK is a family composed of seven isoforms (GRK1–GRK7). Each GRK shows a differential expression pattern. GRK1, GRK4, and GRK7 are expressed in limited tissues. In contrast, GRK2, GRK3, GRK5, and GRK6 are ubiquitously expressed throughout the body. The roles of GRKs in GPCR desensitization are well established. When GPCRs are activated by their agonists, GRKs phosphorylate serine/threonine residues in the intracellular loops and the carboxyl-termini of GPCRs. Phosphorylation promotes translocation of β-arrestins to the receptors and inhibits further G protein activation by interrupting receptor-G protein coupling. The binding of β-arrestins to the receptors also helps to promote receptor internalization by clathrin-coated pits. Thus, the GRK-catalyzed phosphorylation and subsequent binding of β-arrestin to GPCRs are believed to be the common mechanism of GPCR desensitization and internalization. Recent studies have revealed that GRKs are also involved in the β-arrestin-mediated signaling pathway. The GRK-mediated phosphorylation of the receptors plays opposite roles in conventional G protein- and β-arrestin-mediated signaling. The GRK-catalyzed phosphorylation of the receptors results in decreased G protein-mediated signaling, but it is necessary for β-arrestin-mediated signaling. Agonists that selectively activate GRK/β-arrestin-dependent signaling without affecting G protein signaling are known as β-arrestin-biased agonists. Biased agonists are expected to have potential therapeutic benefits for various diseases due to their selective activation of favorable physiological responses or avoidance of the side effects of drugs. Furthermore, GRKs are recognized as signaling mediators that are independent of either G protein- or β-arrestin-mediated pathways. GRKs can phosphorylate non-GPCR substrates, and this is found to be involved in various physiological responses, such as cell motility, development, and inflammation. In addition to these effects, our group revealed that GRK6 expressed in macrophages mediates the removal of apoptotic cells (engulfment) in a kinase activity-dependent manner. These studies revealed that GRKs block excess stimulus and also induce cellular responses. Here, we summarized the involvement of GRKs in β-arrestin-mediated and G protein-independent signaling pathways.

Introduction

G protein-coupled receptor kinases (GRKs) were originally identified as the kinases that phosphorylate and desensitize agonist-bound G protein-coupled receptors (GPCRs) [1]. The phosphorylation of agonist-bound GPCR by GRKs leads to the translocation and binding of β-arrestins to the receptors, inhibiting further G protein activation by blocking receptor-G protein coupling [2, 3]. The phosphorylation of GPCR by GRKs and the binding of β-arrestins to the receptors also promote agonist-bound GPCR internalization [46]. Thus, the GRK-catalyzed phosphorylation and binding of β-arrestin to the receptors are believed to be the common mechanism of GPCR desensitization [7, 8]. GPCR desensitization is important for maintaining homeostasis, as malfunction of the desensitization process could cause various diseases such as heart failure [911], inappropriate diuresis [12], asthma [13], Parkinson’s disease [14], and autoimmune disease [15]. Thus, GRKs play an essential role in maintaining cells and tissues in normal states.

GRKs are composed of seven isoforms (GRK1–GRK7) [16]. Although each GRK is involved in GPCR desensitization, some differences are observed in the expression, structure, and functions of GRKs [17, 18]. GRK1, GRK4, and GRK7 are expressed in limited tissues. GRK1 and GRK7 are expressed in the retina [1921], and GRK4 is expressed in the testis [22]. In contrast, other GRKs (GRK2, GRK3, GRK5, and GRK6) are expressed ubiquitously throughout the body [2326]. Based on sequence homology, the GRK family can be divided into the three following subfamilies: the GRK1 subfamily composed of GRK1 and GRK7, the GRK2 subfamily composed of GRK2 and GRK3, and the GRK4 subfamily composed of GRK4, GRK5, and GRK6. All GRK isoforms share similar domains, which are composed of an amino-terminal domain unique to the GRK family of kinases, a regulator of G protein signaling homology domain; which could regulate GPCR signaling by phosphorylation-independent mechanisms [2729], a serine/threonine protein kinase domain, and a carboxyl-terminal domain [30]. The amino-terminal domain of GRK2 interacts with the G protein βγ subunit, whereas that of GRK4, GRK5, and GRK6 interacts with phosphatidylinositol 4,5-bisphosphate (PIP2) [18, 31, 32]. Sequence divergence has been observed among GRKs in the carboxyl-terminal domain; GRK1 and GRK7 have short prenylation sequences [33], GRK2 and GRK3 have pleckstrin homology domains that interact with G protein βγ subunits [34, 35] and PIP2 [36], and the members of the GRK4 subfamily have palmitoylation sites [22, 37] and/or positively charged lipid-binding elements [38, 39]. The carboxyl-termini of GRKs appear to be important for the localization and translocation of kinases to the membrane by means of posttranslational modifications or sites of interaction with lipids or membrane proteins [39]. The GRK4 subfamily (GRK4, GRK5, and GRK6) have been found to contain a functional nuclear localization signal (NLS) [3941], and GRK5 and GRK6 have been shown to bind to DNA [40]. These properties could lead to functional diversification among GRKs. In fact, knockout mice for each GRK showed different phenotypes. GRK2 knockout mice are embryonic lethal [42], but knockout mice for other GRKs are born and develop normally. However, GRK6 knockout mice show dopaminergic supersensitivity [14] and develop autoimmune disease [43]. Further studies using knockout mice would reveal functional diversification among GRKs.

Involvement of GRKs in G protein-independent signaling

Recent studies have revealed that GRKs are involved not only in GPCR desensitization but also in G protein-independent signaling [44, 45]. G protein-independent signaling requires GRKs and β-arrestins. GRK5 or GRK6 is required for G protein-independent extracellular signal-regulated kinase (ERK) activation by angiotensin II type 1A receptor (AT1AR) [46], vasopressin receptor 2 (V2R) [47], and β2-adrenergic receptor (β2-AR) [48]. GRK/β-arrestin-dependent signaling induces physiological responses that are different from G protein-mediated responses [4951]. The activation of one of these signaling pathways could be beneficial, whereas the activation of the other signaling pathway could be harmful [5255]. These findings have led to the identification and synthesis of agonists that selectively activate either G protein- or GRK/β-arrestin-dependent signaling [56, 57]. Thus far, some agonists have been found to activate either G protein- [58] or GRK/β-arrestin-dependent signaling [59, 60] by their own GPCRs. These agonists that can selectively activate only one signaling pathway are known as “biased agonists” [61] and have been proposed to be preferred for the treatment of various diseases [62]. As different conformational changes are induced in the cytoplasmic domain of GPCRs by the binding of full agonists and antagonists, biased agonists could induce the conformational state that selectively activates one of two signaling pathways [63] (Figure  1). However, the recent development of bioluminescent resonance energy transfer (BRET)-based G protein activation biosensors enabled the detection of G protein activation by stimulation with a GRK/β-arrestin-biased agonist [64]. It demonstrated that GRK/β-arrestin-biased agonists can activate G protein-mediated pathway, although the degree of activation is low. However, it is possible that the different conformational states of GPCRs selectively recruit a specific GRK, leading to the activation of GRK/β-arrestin-dependent signaling pathways.

Figure 1
figure 1

GRKs are involved in cellular signaling that is independent of G protein activation. Biased agonist activates either G protein signaling or GRK/β-arrestin-dependent signaling. Each agonist promotes distinct conformational changes of GPCRs. Unbiased agonists activate both G protein signaling and GRK/β-arrestin-dependent signaling, whereas biased agonists activate either G protein- or GRK/β-arrestin-dependent signaling as shown in bold arrows. Physiological responses mediated by GRK/β-arrestin-dependent signaling are believed to be distinct from those by G protein activation.

The mechanism by which GRKs determine whether to promote GPCR desensitization or G protein-independent signaling remains unclear. Several studies have focused on the GRK subfamily that mediates desensitization or GRK/β-arrestin signaling [46, 47, 65, 66]. It has been shown that the phosphorylation of AT1AR by GRK2 and GRK3 induces GPCR desensitization and internalization, whereas phosphorylation by GRK5 leads to β-arrestin-dependent ERK activation [46]. It has also been reported that GRK2 and GRK3 promote V2R desensitization, and GRK5 and GRK6 are responsible for the phosphorylation of ERK [47]. These studies demonstrate that different GRKs promote different functions of GPCRs, desensitization or signal transduction. Furthermore, the type of ligand is also important to determine whether to promote desensitization or signaling by GRKs. CC chemokine ligands 19 and 21 (CCL19 and CCL21) are the ligands of CC chemokine receptor type 7 (CCR7) that activate different GRK subfamilies, leading to receptor desensitization or signaling. CCL19 induces GPCR desensitization that was mediated by GRK3 and GRK6, whereas CCL21 promotes GRK/β-arrestin-mediated signaling that was dependent on GRK6 [65]. This result suggests that the ligands of GPCRs selectively activate specific GRKs, and activated GRKs then determine whether to promote GPCR desensitization or signaling. Although it is not fully understood how different ligands selectively recruit specific GRKs to the receptors, different conformational changes induced by different ligands may determine which GRK is selectively recruited to the receptors [63].

It has also been proposed that a differential phosphorylation pattern is essential for determining whether to promote GPCR desensitization or signaling. Butcher et al. found that different tissues and cells exhibit a differential GPCR phosphorylation pattern of the M3 muscarinic receptor [67]. However, they did not evaluate which kinases; such as protein kinase A, protein kinase C, and GRKs; are involved in the phosphorylation of the receptors. Nobles et al. demonstrated that different GRKs phosphorylate different sets of serine/threonine residues in the carboxyl-terminus of GPCR, and this determines whether desensitization or signaling is promoted by the receptor [68]. They found that GRK2 and GRK6 phosphorylate different sites in β2-AR, which determines the different functions of β-arrestin, β-arrestin-mediated desensitization or signaling [68]. Thus, the GPCR phosphorylation pattern (which is proposed as “phosphorylation barcoding”) [69] would be an important factor for the promotion of desensitization or signaling by GRKs.

Thus, the conformational changes of GPCRs and phosphorylation pattern of GPCRs could be important for G protein activation, GPCR desensitization, and GRK/β-arrestin-mediated signaling. Although “phosphorylation barcoding” was recently proposed as a key factor for determining whether to promote desensitization or GRK/β-arrestin-mediated signaling, it remains to be elucidated how each GRK phosphorylates specific serine/threonine residues. The identification of the consensus phosphorylation sequences for each GRK would be meaningful to understand how GRKs regulate GPCR desensitization and GRK/β-arrestin-dependent signaling.

Physiological importance of GRK/β-arrestin-biased agonist

Many agonists can usually activate both G protein- and β-arrestin-mediated signaling pathways [62]. A biased agonist is defined as an agonist that selectively activates only one of these pathways [61]. Thus far, an increasing number of GPCR agonists have been found to function as biased agonists. It also suggests the potential use of biased agonists as a therapeutic agent [53, 62]. Among various reports, biased agonists for β-ARs are well studied in terms of clinical use [70, 71]. Noma et al. demonstrated that GRK/β-arrestin-biased signaling by β1-AR elicits cardioprotective effects in vivo [55]. GRK phosphorylates serine/threonine residues in the carboxyl-terminus of β1-AR. They substituted these serine/threonine residues with alanine and produced transgenic mice expressing mutant β1-AR in the heart (GRK-β1-AR TG). They also produced transgenic mice expressing wild-type β1-AR in the heart (WT-β1-AR TG). When these mice were subjected to chronic exposure of isoproterenol, GRK-β1-AR TG mice showed a significantly higher number of apoptotic cells than WT-β1-AR TG mice. This resulted in decreased cardiac performance in GRK-β1-AR TG mice. They also demonstrated that epidermal growth factor receptor (EGFR) transactivation by GRK/β-arrestin-mediated, but not G protein-mediated, signaling is important for cardioprotective effects. As the chronic activation of Gs signaling by β1-AR is reported to be cardiotoxic, β-adrenergic blocking agents are beneficial for the treatment of heart failure [72]. They suggested that GRK/β-arrestin-biased agonists, which also antagonize Gs signaling, are more suitable for the treatment of heart failure. Among 20 β-adrenergic blocking agents, alprenolol and carvedilol have been identified as biased agonists for β1-AR [60], and carvedilol has been clinically used for the treatment of heart failure. Alprenolol and carvedilol could induce EGFR transactivation in a GRK/β-arrestin-dependent manner. However, it remains to be determined whether alprenolol-mediated G protein-independent signaling also has cardioprotective effects against heart failure. In contrast, our group recently reported that the long-term oral administration of metoprolol, a β-adrenergic blocking agent, induces cardiac fibrosis in mice by β1-AR in a GRK5/β-arrestin2-dependent manner without G protein activation [73]. Fibrosis is the excessive deposition of extracellular matrix, such as collagen and fibronectin, and is believed to be deleterious for cardiac function. In contrast to carvedilol and alprenolol, metoprolol does not promote the EGFR internalization and activation [60, 73]. This suggests that metoprolol activates biased signaling in a different manner from that of carvedilol and alprenolol.

AT1AR has also been well studied as a model GPCR to analyze biased agonists [70, 71]. Biased agonists that selectively activate GRK/β-arrestin-dependent signaling in cardiomyocytes have been reported to promote cardiomyocyte growth and cardiac hypertrophy and affect cardiac performance [74]. [Sar1, Ile4, Ile8] angiotensin II (SII), TRV120023, and TRV120027 have been developed as GRK/β-arrestin-biased agonists for AT1AR, and SII has been frequently used for the study of G protein-independent signaling of AT1AR [54, 59, 64, 75, 76]. Both SII and TRV120027 have been shown to increase cardiac contractility in vitro and in vivo [59, 75]. In contrast, TRV120023 promotes the survival of cardiomyocytes during ischemia/reperfusion injury in vivo [54]. Thus, biased agonist-promoted GRK/β-arrestin-dependent signaling by AT1AR could be beneficial for the heart under physiological and pathological conditions. However, it remains to be determined which GRKs are involved in AT1AR-mediated biased signaling and which molecules downstream of GRKs and β-arrestins are responsible for signaling.

Interaction of GRKs with non-GPCR proteins

In addition to the role of GRKs in GRK/β-arrestin-dependent signaling, it has been recognized that GRKs also interact with non-GPCR proteins [30, 77]. Non-GPCR proteins that interact with GRKs include single-transmembrane receptors [78, 79], cytosolic proteins [8082], and nuclear proteins [83, 84] (Figure  2). Many studies demonstrated that the interaction of GRKs with intracellular non-GPCR proteins affects various signaling pathways [80, 8589]. This includes inflammation [85, 86], cell motility [81, 90], and cell cycle [91, 92] (Table  1). However, it remains unclear whether these atypical signaling pathways have physiological significance in vivo.

Figure 2
figure 2

Binding partners with GRKs. GRKs regulate diverse signaling pathways by the interaction with intracellular proteins, resulting in various physiological responses.

Table 1 Interactions of each GRKs with intracellular proteins

Several reports have suggested that the interaction of GRK with intracellular non-GPCRs affects signaling pathways. It has been reported that GRK2 negatively regulates CCL2-induced ERK activation by interacting with mitogen-activated protein kinase kinase (MEK) [93]. Other signaling pathways, including the nuclear factor-kappa B (NF-κB) pathway [85, 86], insulin signaling [94], and Smad signaling [87], have also been modulated by the interaction of GRKs with non-GPCR proteins. Although GRKs exhibit kinase activity, GRKs can interact with intracellular proteins and modulate downstream signaling pathways in a kinase activity-independent manner [9597], indicating that GRKs can act as scaffold proteins. Because GRKs are composed of several domains other than a kinase domain, these regulatory domains may determine phosphorylation-independent signaling of GRKs.

Interactions between GRKs and intracellular proteins occurred at various sites including the outer membrane of the mitochondria and nucleus in addition to the plasma membrane and cytosol. For example, GRK2 was shown to localize in the mitochondria [98] and to interact with heat shock protein 90, a known mitochondrial chaperone [99]. A recent study further revealed that the ERK-mediated phosphorylation of GRK2 at Ser670 was important for the localization of GRK2 in the mitochondria, and this localization induced Ca2+-induced opening of the mitochondrial permeability transition pore after ischemic injury, which promoted cardiomyocyte death [100]. It was also shown that GRK2 was detected in the damaged mitochondria in the brain [101]. These reports suggested the crucial role of GRK2 in the mitochondria. In contrast, GRK5 was shown to localize in the nucleus and phosphorylated class II histone deacetylase 5 (HDAC5) [83]. This phosphorylation enhanced HDAC5 activity, leading to the export of HDAC from the nucleus. This resulted in the induction of myocyte enhancer factor-2 derepression and maladaptive cardiac hypertrophy. GRK5 was also reported to interact with the inhibitor of kappa B alpha (IκBα). Interaction between GRK5 and IκBα promoted the nuclear accumulation of IκBα, which resulted in the inhibition of NF-κB activity [86]. However, another group reported opposite results and showed that GRK5 enhanced NF-κB activity by promoting the phosphorylation and degradation of IκBα [85]. The NLS of GRK5 was important for nuclear function of GRK5. Therefore, other GRKs such as GRK4 and GRK6 (the GRK4 subfamily) may have similar functions in the nucleus as GRK5 because they also have their own NLS [40].

Some studies have reported the mechanism by which GRKs are activated and promote signaling by non-GPCR proteins [30]. It has been shown that GRK2 or GRK5 phosphorylates tubulin [102104], and the phosphorylation level of tubulin by GRK2 is increased by β-AR stimulation [103]. Furthermore, GRK2 also phosphorylates insulin receptor substrate (IRS)-1, the phosphorylation activity of which is regulated by endothelin-1, an agonist of endothelin type A receptor [94]. These reports suggest that the binding of GRKs to activated GPCR could promote the interaction with intracellular non-GPCR proteins and stimulate the GRK-catalyzed phosphorylation of intracellular non-GPCR proteins. Participation of GRK2 in cellular regulation is also modulated by another kinase. The phosphorylation of GRK2 by cyclin-dependent kinase 2 (CDK2) transiently downregulates GRK2 expression, and the CDK2-catalyzed phosphorylation of GRK2 affects cell cycle progression [91]. In addition to phosphorylation, Cys of GRK2 at position 340 is modified by nitric oxide (NO), and the S-nitrosylation of GRK2 is critical for the downregulation of β-AR signaling in vitro and in vivo [105]. A cell-permeable NO donor, S-nitrosocysteine (CysNO), downregulated β-AR signaling by inhibiting the GRK2-catalyzed phosphorylation of β-AR and binding of β-arrestin to β-AR. Thus, posttranslational modification of GRKs may be another important factor for the regulation of GRK-mediated signaling.

Recent studies have suggested an in vivo significance of the interaction between GRK and intracellular non-GPCR proteins. GRK2 interacts with Akt and inhibits endothelial NO synthase activity and NO production, resulting in less severe portal hypertension in GRK2-deficient mice after liver injury [82]. GRK5 phosphorylates p53 and inhibits DNA damage-induced apoptosis in vitro and in vivo [106]. Although the mechanism is unknown, GRK2 was recently found to be involved in developmental and tumoral vascularization in mice [107]. That study was performed using endothelium-specific Grk2-knockout mice [107] because global ablation of GRK2 resulted in embryonic lethality [42]. Furthermore, it was recently revealed that Grk5l, which is the closest homolog of GRK5 in zebrafish, controlled heart formation during early development [108]. In their report, Grk5l was found to interact with Raptor, which is a component of mammalian target of rapamycin (mTOR) complex 1. Subsequently, the interaction of Grk5l with Raptor inhibited mTOR signaling by an unknown mechanism. Further studies are required to reveal undefined in vivo functions of GRKs with new binding partners.

Although the abovementioned studies have mainly focused on GRK2 and GRK5, the importance of the interaction of other GRK subfamilies with intracellular proteins remains poorly understood. GRK6 was recently found to mediate the removal of apoptotic cells (engulfment) and the clearance of senescent red blood cells through a new engulfment pathway [43]. Insufficient engulfment in GRK6-deficient mice resulted in the development of an autoimmune disease-like phenotype [43].

Conclusions

It has become clear that GRKs are multifunctional proteins that interact not only with GPCRs but also with intracellular non-GPCR proteins. However, several issues remain to be resolved in future studies. One issue is the mechanism by which GRKs phosphorylate specific serine/threonine residues in GPCRs and non-GPCR proteins. Although GRKs can phosphorylate a large number of proteins, the consensus sequence of the phosphorylation site for each GRK has not been firmly established [109]. The second issue is the identification of molecules upstream of GRKs that are responsible for the increased phosphorylation of non-GPCR proteins. It is also important to elucidate signaling cascades from GRKs to cellular events. Another issue is the mechanisms for regulating the expression and activity of each GRK. We found that GRK6 expression was increased in MRL/Lpr mice, a murine model of systemic lupus erythematosus (SLE), and the autopsied spleens from SLE patients [43]. The changes in expression levels of GRKs were also found in patients with heart failure [110], schizophrenia [111], and depression [112]. However, it is unknown how these changes in expression cause these diseases. In contrast, it was revealed that overexpression of GRK2ct (also known as β-ARKct), a peptide inhibitor composed of the last 194 amino acids of GRK2, was successful for the prevention of heart failure through the inhibition of mitochondrial translocation [9, 113115]. These studies suggested that the inhibitors of GRKs could be effective for the treatment of heart failure [116]. Instead of the peptide inhibitor GRK2ct, chemical compounds are a more promising tool for treating heart failure. Recent reports revealed that the development of selective inhibitors against GRK2 is possible [117, 118]. It is interesting to examine whether selective inhibition of GRK2 using chemical compounds [117, 118] is beneficial for the abovementioned diseases.

References

  1. Benovic JL, Kuhn H, Weyand I, Codina J, Caron MG, Lefkowitz RJ: Functional desensitization of the isolated beta-adrenergic receptor by the beta-adrenergic receptor kinase: potential role of an analog of the retinal protein arrestin (48-kDa protein). Proc Natl Acad Sci U S A 1987, 84:8879–8882.

    PubMed Central  PubMed  CAS  Google Scholar 

  2. Bouvier M, Hausdorff WP, De Blasi A, O’Dowd BF, Kobilka BK, Caron MG, Lefkowitz RJ: Removal of phosphorylation sites from the beta 2-adrenergic receptor delays onset of agonist-promoted desensitization. Nature 1988, 333:370–373.

    PubMed  CAS  Google Scholar 

  3. Lohse MJ, Benovic JL, Codina J, Caron MG, Lefkowitz RJ: Beta-arrestin: a protein that regulates beta-adrenergic receptor function. Science 1990, 248:1547–1550.

    PubMed  CAS  Google Scholar 

  4. Ferguson SS, Downey WE 3rd, Colapietro AM, Barak LS, Menard L, Caron MG: Role of beta-arrestin in mediating agonist-promoted G protein-coupled receptor internalization. Science 1996, 271:363–366.

    PubMed  CAS  Google Scholar 

  5. Tsuga H, Kameyama K, Haga T, Kurose H, Nagao T: Sequestration of muscarinic acetylcholine receptor m2 subtypes. Facilitation by G protein-coupled receptor kinase (GRK2) and attenuation by a dominant-negative mutant of GRK2. J Biol Chem 1994, 269:32522–32527.

    PubMed  CAS  Google Scholar 

  6. Ferguson SS, Menard L, Barak LS, Koch WJ, Colapietro AM, Caron MG: Role of phosphorylation in agonist-promoted beta 2-adrenergic receptor sequestration. Rescue of a sequestration-defective mutant receptor by beta ARK1. J Biol Chem 1995, 270:24782–24789.

    PubMed  CAS  Google Scholar 

  7. Reiter E, Lefkowitz RJ: GRKs and beta-arrestins: roles in receptor silencing, trafficking and signaling. Trends Endocrinol Metab 2006, 17:159–165.

    PubMed  CAS  Google Scholar 

  8. Ferguson SS: Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol Rev 2001, 53:1–24.

    PubMed  CAS  Google Scholar 

  9. Rockman HA, Chien KR, Choi DJ, Iaccarino G, Hunter JJ, Ross J Jr, Lefkowitz RJ, Koch WJ: Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice. Proc Natl Acad Sci U S A 1998, 95:7000–7005.

    PubMed Central  PubMed  CAS  Google Scholar 

  10. Tachibana H, Naga Prasad SV, Lefkowitz RJ, Koch WJ, Rockman HA: Level of beta-adrenergic receptor kinase 1 inhibition determines degree of cardiac dysfunction after chronic pressure overload-induced heart failure. Circulation 2005, 111:591–597.

    PubMed  CAS  Google Scholar 

  11. Lymperopoulos A, Rengo G, Funakoshi H, Eckhart AD, Koch WJ: Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure. Nat Med 2007, 13:315–323.

    PubMed  CAS  Google Scholar 

  12. Barak LS, Oakley RH, Laporte SA, Caron MG: Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus. Proc Natl Acad Sci U S A 2001, 98:93–98.

    PubMed Central  PubMed  CAS  Google Scholar 

  13. Wang WC, Mihlbachler KA, Brunnett AC, Liggett SB: Targeted transgenesis reveals discrete attenuator functions of GRK and PKA in airway beta2-adrenergic receptor physiologic signaling. Proc Natl Acad Sci U S A 2009, 106:15007–15012.

    PubMed Central  PubMed  CAS  Google Scholar 

  14. Gainetdinov RR, Bohn LM, Sotnikova TD, Cyr M, Laakso A, Macrae AD, Torres GE, Kim KM, Lefkowitz RJ, Caron MG, Premont RT: Dopaminergic supersensitivity in G protein-coupled receptor kinase 6-deficient mice. Neuron 2003, 38:291–303.

    PubMed  CAS  Google Scholar 

  15. Balabanian K, Lagane B, Pablos JL, Laurent L, Planchenault T, Verola O, Lebbe C, Kerob D, Dupuy A, Hermine O, Nicolas JF, Latger-Cannard V, Bensoussan D, Bordigoni P, Baleux F, Le Deist F, Virelizier JL, Arenzana-Seisdedos F, Bachelerie F: WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12. Blood 2005, 105:2449–2457.

    PubMed  CAS  Google Scholar 

  16. Pitcher JA, Freedman NJ, Lefkowitz RJ: G protein-coupled receptor kinases. Annu Rev Biochem 1998, 67:653–692.

    PubMed  CAS  Google Scholar 

  17. Penela P, Ribas C, Mayor F: Mechanisms of regulation of the expression and function of G protein-coupled receptor kinases. Cell Signal 2003, 15:973–981.

    PubMed  CAS  Google Scholar 

  18. Willets JM, Challiss RA, Nahorski SR: Non-visual GRKs: are we seeing the whole picture? Trends Pharmacol Sci 2003, 24:626–633.

    PubMed  CAS  Google Scholar 

  19. Hisatomi O, Matsuda S, Satoh T, Kotaka S, Imanishi Y, Tokunaga F: A novel subtype of G-protein-coupled receptor kinase, GRK7, in teleost cone photoreceptors. FEBS Lett 1998, 424:159–164.

    PubMed  CAS  Google Scholar 

  20. Weiss ER, Raman D, Shirakawa S, Ducceschi MH, Bertram PT, Wong F, Kraft TW, Osawa S: The cloning of GRK7, a candidate cone opsin kinase, from cone- and rod-dominant mammalian retinas. Mol Vis 1998, 4:27.

    PubMed  CAS  Google Scholar 

  21. Weller M, Virmaux N, Mandel P: Light-stimulated phosphorylation of rhodopsin in the retina: the presence of a protein kinase that is specific for photobleached rhodopsin. Proc Natl Acad Sci U S A 1975, 72:381–385.

    PubMed Central  PubMed  CAS  Google Scholar 

  22. Premont RT, Macrae AD, Stoffel RH, Chung N, Pitcher JA, Ambrose C, Inglese J, MacDonald ME, Lefkowitz RJ: Characterization of the G protein-coupled receptor kinase GRK4. Identification of four splice variants. J Biol Chem 1996, 271:6403–6410.

    PubMed  CAS  Google Scholar 

  23. Benovic JL, DeBlasi A, Stone WC, Caron MG, Lefkowitz RJ: Beta-adrenergic receptor kinase: primary structure delineates a multigene family. Science 1989, 246:235–240.

    PubMed  CAS  Google Scholar 

  24. Benovic JL, Onorato JJ, Arriza JL, Stone WC, Lohse M, Jenkins NA, Gilbert DJ, Copeland NG, Caron MG, Lefkowitz RJ: Cloning, expression, and chromosomal localization of beta-adrenergic receptor kinase 2. A new member of the receptor kinase family. J Biol Chem 1991, 266:14939–14946.

    PubMed  CAS  Google Scholar 

  25. Kunapuli P, Benovic JL: Cloning and expression of GRK5: a member of the G protein-coupled receptor kinase family. Proc Natl Acad Sci U S A 1993, 90:5588–5592.

    PubMed Central  PubMed  CAS  Google Scholar 

  26. Benovic JL, Gomez J: Molecular cloning and expression of GRK6. A new member of the G protein-coupled receptor kinase family. J Biol Chem 1993, 268:19521–19527.

    PubMed  CAS  Google Scholar 

  27. Carman CV, Parent JL, Day PW, Pronin AN, Sternweis PM, Wedegaertner PB, Gilman AG, Benovic JL, Kozasa T: Selective regulation of Galpha(q/11) by an RGS domain in the G protein-coupled receptor kinase, GRK2. J Biol Chem 1999, 274:34483–34492.

    PubMed  CAS  Google Scholar 

  28. Sallese M, Mariggio S, D’Urbano E, Iacovelli L, De Blasi A: Selective regulation of Gq signaling by G protein-coupled receptor kinase 2: direct interaction of kinase N terminus with activated galphaq. Mol Pharmacol 2000, 57:826–831.

    PubMed  CAS  Google Scholar 

  29. Dhami GK, Anborgh PH, Dale LB, Sterne-Marr R, Ferguson SS: Phosphorylation-independent regulation of metabotropic glutamate receptor signaling by G protein-coupled receptor kinase 2. J Biol Chem 2002, 277:25266–25272.

    PubMed  CAS  Google Scholar 

  30. Gurevich EV, Tesmer JJ, Mushegian A, Gurevich VV: G protein-coupled receptor kinases: more than just kinases and not only for GPCRs. Pharmacol Ther 2012, 133:40–69.

    PubMed Central  PubMed  CAS  Google Scholar 

  31. Eichmann T, Lorenz K, Hoffmann M, Brockmann J, Krasel C, Lohse MJ, Quitterer U: The amino-terminal domain of G-protein-coupled receptor kinase 2 is a regulatory Gbeta gamma binding site. J Biol Chem 2003, 278:8052–8057.

    PubMed  CAS  Google Scholar 

  32. Premont RT, Macrae AD, Aparicio SA, Kendall HE, Welch JE, Lefkowitz RJ: The GRK4 subfamily of G protein-coupled receptor kinases. Alternative splicing, gene organization, and sequence conservation. J Biol Chem 1999, 274:29381–29389.

    PubMed  CAS  Google Scholar 

  33. Inglese J, Koch WJ, Caron MG, Lefkowitz RJ: Isoprenylation in regulation of signal transduction by G-protein-coupled receptor kinases. Nature 1992, 359:147–150.

    PubMed  CAS  Google Scholar 

  34. Pitcher JA, Inglese J, Higgins JB, Arriza JL, Casey PJ, Kim C, Benovic JL, Kwatra MM, Caron MG, Lefkowitz RJ: Role of beta gamma subunits of G proteins in targeting the beta-adrenergic receptor kinase to membrane-bound receptors. Science 1992, 257:1264–1267.

    PubMed  CAS  Google Scholar 

  35. Daaka Y, Pitcher JA, Richardson M, Stoffel RH, Robishaw JD, Lefkowitz RJ: Receptor and G betagamma isoform-specific interactions with G protein-coupled receptor kinases. Proc Natl Acad Sci U S A 1997, 94:2180–2185.

    PubMed Central  PubMed  CAS  Google Scholar 

  36. Pitcher JA, Touhara K, Payne ES, Lefkowitz RJ: Pleckstrin homology domain-mediated membrane association and activation of the beta-adrenergic receptor kinase requires coordinate interaction with G beta gamma subunits and lipid. J Biol Chem 1995, 270:11707–11710.

    PubMed  CAS  Google Scholar 

  37. Stoffel RH, Randall RR, Premont RT, Lefkowitz RJ, Inglese J: Palmitoylation of G protein-coupled receptor kinase, GRK6. Lipid modification diversity in the GRK family. J Biol Chem 1994, 269:27791–27794.

    PubMed  CAS  Google Scholar 

  38. Thiyagarajan MM, Stracquatanio RP, Pronin AN, Evanko DS, Benovic JL, Wedegaertner PB: A predicted amphipathic helix mediates plasma membrane localization of GRK5. J Biol Chem 2004, 279:17989–17995.

    PubMed  CAS  Google Scholar 

  39. Jiang X, Benovic JL, Wedegaertner PB: Plasma membrane and nuclear localization of G protein coupled receptor kinase 6A. Mol Biol Cell 2007, 18:2960–2969.

    PubMed Central  PubMed  CAS  Google Scholar 

  40. Johnson LR, Robinson JD, Lester KN, Pitcher JA: Distinct structural features of G protein-coupled receptor kinase 5 (GRK5) regulate its nuclear localization and DNA-binding ability. PloS One 2013, 8:e62508.

    PubMed Central  PubMed  CAS  Google Scholar 

  41. Johnson LR, Scott MG, Pitcher JA: G protein-coupled receptor kinase 5 contains a DNA-binding nuclear localization sequence. Mol Cell Biol 2004, 24:10169–10179.

    PubMed Central  PubMed  CAS  Google Scholar 

  42. Matkovich SJ, Diwan A, Klanke JL, Hammer DJ, Marreez Y, Odley AM, Brunskill EW, Koch WJ, Schwartz RJ, Dorn GW 2nd: Cardiac-specific ablation of G-protein receptor kinase 2 redefines its roles in heart development and beta-adrenergic signaling. Circ Res 2006, 99:996–1003.

    PubMed  CAS  Google Scholar 

  43. Nakaya M, Tajima M, Kosako H, Nakaya T, Hashimoto A, Watari K, Nishihara H, Ohba M, Komiya S, Tani N, Nishida M, Taniguchi H, Sato Y, Matsumoto M, Tsuda M, Kuroda M, Inoue K, Kurose H: GRK6 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance. Nat Commun 2013, 4:1532.

    PubMed Central  PubMed  Google Scholar 

  44. Lefkowitz RJ, Shenoy SK: Transduction of receptor signals by beta-arrestins. Science 2005, 308:512–517.

    PubMed  CAS  Google Scholar 

  45. Ibrahim IAAEH, Kurose H: β-arrestin-mediated signaling improves the efficacy of therapeutics. J Pharmacol Sci 2012, 118:408–412.

    PubMed  CAS  Google Scholar 

  46. Kim J, Ahn S, Ren XR, Whalen EJ, Reiter E, Wei H, Lefkowitz RJ: Functional antagonism of different G protein-coupled receptor kinases for beta-arrestin-mediated angiotensin II receptor signaling. Proc Natl Acad Sci U S A 2005, 102:1442–1447.

    PubMed Central  PubMed  CAS  Google Scholar 

  47. Ren XR, Reiter E, Ahn S, Kim J, Chen W, Lefkowitz RJ: Different G protein-coupled receptor kinases govern G protein and beta-arrestin-mediated signaling of V2 vasopressin receptor. Proc Natl Acad Sci U S A 2005, 102:1448–1453.

    PubMed Central  PubMed  CAS  Google Scholar 

  48. Shenoy SK, Drake MT, Nelson CD, Houtz DA, Xiao K, Madabushi S, Reiter E, Premont RT, Lichtarge O, Lefkowitz RJ: Beta-arrestin-dependent, G protein-independent ERK1/2 activation by the beta2 adrenergic receptor. J Biol Chem 2006, 281:1261–1273.

    PubMed  CAS  Google Scholar 

  49. DeWire SM, Ahn S, Lefkowitz RJ, Shenoy SK: β-arrestins and cell signaling. Annu Rev Physiol 2007, 69:483–510.

    PubMed  CAS  Google Scholar 

  50. Luttrell LM, Gesty-Palmer D: Beyond desensitization: physiological relevance of arrestin-dependent signaling. Pharmacol Rev 2010, 62:305–330.

    PubMed Central  PubMed  CAS  Google Scholar 

  51. Schmid CL, Bohn LM: Physiological and pharmacological implications of beta-arrestin regulation. Pharmacol Ther 2009, 121:285–293.

    PubMed Central  PubMed  CAS  Google Scholar 

  52. Walters RW, Shukla AK, Kovacs JJ, Violin JD, DeWire SM, Lam CM, Chen JR, Muehlbauer MJ, Whalen EJ, Lefkowitz RJ: Beta-arrestin1 mediates nicotinic acid-induced flushing, but not its antilipolytic effect, in mice. J Clin Investig 2009, 119:1312–1321.

    PubMed Central  PubMed  CAS  Google Scholar 

  53. Gesty-Palmer D, Flannery P, Yuan L, Corsino L, Spurney R, Lefkowitz RJ, Luttrell LM: A beta-arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G protein activation. Sci Transl Med 2009, 1:1ra1.

    PubMed Central  PubMed  Google Scholar 

  54. Kim KS, Abraham D, Williams B, Violin JD, Mao L, Rockman HA: Beta-arrestin-biased AT1R stimulation promotes cell survival during acute cardiac injury. Am J Physiol Heart Circ Physiol 2012, 303:H1001-H1010.

    PubMed Central  PubMed  CAS  Google Scholar 

  55. Noma T, Lemaire A, Naga Prasad SV, Barki-Harrington L, Tilley DG, Chen J, Le Corvoisier P, Violin JD, Wei H, Lefkowitz RJ, Rockman HA: Beta-arrestin-mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection. J Clin Investig 2007, 117:2445–2458.

    PubMed Central  PubMed  CAS  Google Scholar 

  56. Rajagopal S, Rajagopal K, Lefkowitz RJ: Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nat Rev Drug Discov 2010, 9:373–386.

    PubMed Central  PubMed  CAS  Google Scholar 

  57. Kenakin T, Miller LJ: Seven transmembrane receptors as shapeshifting proteins: the impact of allosteric modulation and functional selectivity on new drug discovery. Pharmacol Rev 2010, 62:265–304.

    PubMed Central  PubMed  CAS  Google Scholar 

  58. Quoyer J, Janz JM, Luo J, Ren Y, Armando S, Lukashova V, Benovic JL, Carlson KE, Hunt SW 3rd, Bouvier M: Pepducin targeting the C-X-C chemokine receptor type 4 acts as a biased agonist favoring activation of the inhibitory G protein. Proc Natl Acad Sci U S A 2013, 110:E5088-E5097.

    PubMed  CAS  Google Scholar 

  59. Violin JD, DeWire SM, Yamashita D, Rominger DH, Nguyen L, Schiller K, Whalen EJ, Gowen M, Lark MW: Selectively engaging beta-arrestins at the angiotensin II type 1 receptor reduces blood pressure and increases cardiac performance. J Pharmacol Exp Ther 2010, 335:572–579.

    PubMed  CAS  Google Scholar 

  60. Kim IM, Tilley DG, Chen J, Salazar NC, Whalen EJ, Violin JD, Rockman HA: Beta-blockers alprenolol and carvedilol stimulate beta-arrestin-mediated EGFR transactivation. Proc Natl Acad Sci U S A 2008, 105:14555–14560.

    PubMed Central  PubMed  CAS  Google Scholar 

  61. Violin JD, Lefkowitz RJ: Beta-arrestin-biased ligands at seven-transmembrane receptors. Trends Pharmacol Sci 2007, 28:416–422.

    PubMed  CAS  Google Scholar 

  62. Whalen EJ, Rajagopal S, Lefkowitz RJ: Therapeutic potential of beta-arrestin- and G protein-biased agonists. Trends Mol Med 2011, 17:126–139.

    PubMed Central  PubMed  CAS  Google Scholar 

  63. Liu JJ, Horst R, Katritch V, Stevens RC, Wuthrich K: Biased signaling pathways in beta2-adrenergic receptor characterized by 19F-NMR. Science 2012, 335:1106–1110.

    PubMed Central  PubMed  CAS  Google Scholar 

  64. Sauliere A, Bellot M, Paris H, Denis C, Finana F, Hansen JT, Altie MF, Seguelas MH, Pathak A, Hansen JL, Senard JM, Gales C: Deciphering biased-agonism complexity reveals a new active AT(1) receptor entity. Nat Chem Biol 2012, 8:622–630.

    PubMed  CAS  Google Scholar 

  65. Zidar DA, Violin JD, Whalen EJ, Lefkowitz RJ: Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands. Proc Natl Acad Sci U S A 2009, 106:9649–9654.

    PubMed Central  PubMed  CAS  Google Scholar 

  66. Busillo JM, Armando S, Sengupta R, Meucci O, Bouvier M, Benovic JL: Site-specific phosphorylation of CXCR4 is dynamically regulated by multiple kinases and results in differential modulation of CXCR4 signaling. J Biol Chem 2010, 285:7805–7817.

    PubMed Central  PubMed  CAS  Google Scholar 

  67. Butcher AJ, Prihandoko R, Kong KC, McWilliams P, Edwards JM, Bottrill A, Mistry S, Tobin AB: Differential G-protein-coupled receptor phosphorylation provides evidence for a signaling bar code. J Biol Chem 2011, 286:11506–11518.

    PubMed Central  PubMed  CAS  Google Scholar 

  68. Nobles KN, Xiao K, Ahn S, Shukla AK, Lam CM, Rajagopal S, Strachan RT, Huang TY, Bressler EA, Hara MR, Shenoy SK, Gygi SP, Lefkowitz RJ: Distinct phosphorylation sites on the 2-adrenergic receptor establish a barcode that encodes differential functions of -arrestin. Sci Signal 2011, 4:ra51-ra51.

    Google Scholar 

  69. Liggett SB: Phosphorylation barcoding as a mechanism of directing GPCR signaling. Sci Signal 2011, 4:pe36.

    PubMed  CAS  Google Scholar 

  70. DeWire SM, Violin JD: Biased ligands for better cardiovascular drugs: dissecting G-protein-coupled receptor pharmacology. Circ Res 2011, 109:205–216.

    PubMed  CAS  Google Scholar 

  71. Tilley DG: G protein-dependent and G protein-independent signaling pathways and their impact on cardiac function. Circ Res 2011, 109:217–230.

    PubMed Central  PubMed  CAS  Google Scholar 

  72. Bristow MR: Beta-adrenergic receptor blockade in chronic heart failure. Circulation 2000, 101:558–569.

    PubMed  CAS  Google Scholar 

  73. Nakaya M, Chikura S, Watari K, Mizuno N, Mochinaga K, Mangmool S, Koyanagi S, Ohdo S, Sato Y, Ide T, Nishida M, Kurose H: Induction of cardiac fibrosis by beta-blocker in G protein-independent and G protein-coupled receptor kinase 5/beta-arrestin2-dependent Signaling pathways. J Biol Chem 2012, 287:35669–35677.

    PubMed Central  PubMed  Google Scholar 

  74. Zhai P, Yamamoto M, Galeotti J, Liu J, Masurekar M, Thaisz J, Irie K, Holle E, Yu X, Kupershmidt S, Roden DM, Wagner T, Yatani A, Vatner DE, Vatner SF, Sadoshima J: Cardiac-specific overexpression of AT1 receptor mutant lacking G alpha q/G alpha i coupling causes hypertrophy and bradycardia in transgenic mice. J Clin Invest 2005, 115:3045–3056.

    PubMed Central  PubMed  CAS  Google Scholar 

  75. Rajagopal K, Whalen EJ, Violin JD, Stiber JA, Rosenberg PB, Premont RT, Coffman TM, Rockman HA, Lefkowitz RJ: Beta-arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes. Proc Natl Acad Sci U S A 2006, 103:16284–16289.

    PubMed Central  PubMed  CAS  Google Scholar 

  76. Ahn S, Kim J, Hara MR, Ren XR, Lefkowitz RJ: {beta}-arrestin-2 mediates anti-apoptotic signaling through regulation of BAD phosphorylation. J Biol Chem 2009, 284:8855–8865.

    PubMed Central  PubMed  CAS  Google Scholar 

  77. Kurose H: Atypical actions of G protein-coupled receptor kinases. Biomolecules and Therapeutics 2011, 19:390–397.

    CAS  Google Scholar 

  78. Freedman NJ, Kim LK, Murray JP, Exum ST, Brian L, Wu JH, Peppel K: Phosphorylation of the platelet-derived growth factor receptor-beta and epidermal growth factor receptor by G protein-coupled receptor kinase-2. Mechanisms for selectivity of desensitization. J Biol Chem 2002, 277:48261–48269.

    PubMed  CAS  Google Scholar 

  79. Hildreth KL, Wu JH, Barak LS, Exum ST, Kim LK, Peppel K, Freedman NJ: Phosphorylation of the platelet-derived growth factor receptor-beta by G protein-coupled receptor kinase-2 reduces receptor signaling and interaction with the Na(+)/H(+) exchanger regulatory factor. J Biol Chem 2004, 279:41775–41782.

    PubMed  CAS  Google Scholar 

  80. Barthet G, Carrat G, Cassier E, Barker B, Gaven F, Pillot M, Framery B, Pellissier LP, Augier J, Kang DS, Claeysen S, Reiter E, Baneres JL, Benovic JL, Marin P, Bockaert J, Dumuis A: Beta-arrestin1 phosphorylation by GRK5 regulates G protein-independent 5-HT4 receptor signalling. EMBO J 2009, 28:2706–2718.

    PubMed Central  PubMed  CAS  Google Scholar 

  81. Lafarga V, Aymerich I, Tapia O, Mayor F Jr, Penela P: A novel GRK2/HDAC6 interaction modulates cell spreading and motility. EMBO J 2012, 31:856–869.

    PubMed Central  PubMed  CAS  Google Scholar 

  82. Liu S, Premont RT, Kontos CD, Zhu S, Rockey DC: A crucial role for GRK2 in regulation of endothelial cell nitric oxide synthase function in portal hypertension. Nat Med 2005, 11:952–958.

    PubMed  CAS  Google Scholar 

  83. Martini JS, Raake P, Vinge LE, DeGeorge BR Jr, Chuprun JK, Harris DM, Gao E, Eckhart AD, Pitcher JA, Koch WJ: Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes. Proc Natl Acad Sci U S A 2008, 105:12457–12462.

    PubMed Central  PubMed  CAS  Google Scholar 

  84. Parameswaran N, Pao CS, Leonhard KS, Kang DS, Kratz M, Ley SC, Benovic JL: Arrestin-2 and G protein-coupled receptor kinase 5 interact with NFkappaB1 p105 and negatively regulate lipopolysaccharide-stimulated ERK1/2 activation in macrophages. J Biol Chem 2006, 281:34159–34170.

    PubMed  CAS  Google Scholar 

  85. Patial S, Luo J, Porter KJ, Benovic JL, Parameswaran N: G-protein-coupled-receptor kinases mediate TNFalpha-induced NFkappaB signalling via direct interaction with and phosphorylation of IkappaBalpha. Biochem J 2010, 425:169–178.

    CAS  Google Scholar 

  86. Sorriento D, Ciccarelli M, Santulli G, Campanile A, Altobelli GG, Cimini V, Galasso G, Astone D, Piscione F, Pastore L, Trimarco B, Iaccarino G: The G-protein-coupled receptor kinase 5 inhibits NFkappaB transcriptional activity by inducing nuclear accumulation of IkappaB alpha. Proc Natl Acad Sci U S A 2008, 105:17818–17823.

    PubMed Central  PubMed  CAS  Google Scholar 

  87. Ho J, Cocolakis E, Dumas VM, Posner BI, Laporte SA, Lebrun JJ: The G protein-coupled receptor kinase-2 is a TGFbeta-inducible antagonist of TGFbeta signal transduction. EMBO J 2005, 24:3247–3258.

    PubMed Central  PubMed  CAS  Google Scholar 

  88. Peregrin S, Jurado-Pueyo M, Campos PM, Sanz-Moreno V, Ruiz-Gomez A, Crespo P, Mayor F Jr, Murga C: Phosphorylation of p38 by GRK2 at the docking groove unveils a novel mechanism for inactivating p38MAPK. Curr Biol 2006, 16:2042–2047.

    PubMed  CAS  Google Scholar 

  89. Wang L, Gesty-Palmer D, Fields TA, Spurney RF: Inhibition of WNT signaling by G protein-coupled receptor (GPCR) kinase 2 (GRK2). Mol Endocrinol 2009, 23:1455–1465.

    PubMed Central  PubMed  CAS  Google Scholar 

  90. Penela P, Ribas C, Aymerich I, Eijkelkamp N, Barreiro O, Heijnen CJ, Kavelaars A, Sanchez-Madrid F, Mayor F Jr: G protein-coupled receptor kinase 2 positively regulates epithelial cell migration. EMBO J 2008, 27:1206–1218.

    PubMed Central  PubMed  CAS  Google Scholar 

  91. Penela P, Rivas V, Salcedo A, Mayor F Jr: G protein-coupled receptor kinase 2 (GRK2) modulation and cell cycle progression. Proc Natl Acad Sci USA 2010, 107:1118–1123.

    PubMed Central  PubMed  CAS  Google Scholar 

  92. Michal AM, So CH, Beeharry N, Shankar H, Mashayekhi R, Yen TJ, Benovic JL: G Protein-coupled receptor kinase 5 is localized to centrosomes and regulates cell cycle progression. J Biol Chem 2012, 287:6928–6940.

    PubMed Central  PubMed  CAS  Google Scholar 

  93. Jimenez-Sainz MC, Murga C, Kavelaars A, Jurado-Pueyo M, Krakstad BF, Heijnen CJ, Mayor F Jr, Aragay AM: G protein-coupled receptor kinase 2 negatively regulates chemokine signaling at a level downstream from G protein subunits. Mol Biol Cell 2006, 17:25–31.

    PubMed Central  PubMed  CAS  Google Scholar 

  94. Usui I, Imamura T, Babendure JL, Satoh H, Lu JC, Hupfeld CJ, Olefsky JM: G protein-coupled receptor kinase 2 mediates endothelin-1-induced insulin resistance via the inhibition of both Galphaq/11 and insulin receptor substrate-1 pathways in 3T3-L1 adipocytes. Mol Endocrinol 2005, 19:2760–2768.

    PubMed  CAS  Google Scholar 

  95. Shiina T, Arai K, Tanabe S, Yoshida N, Haga T, Nagao T, Kurose H: Clathrin box in G protein-coupled receptor kinase 2. J Biol Chem 2001, 276:33019–33026.

    PubMed  CAS  Google Scholar 

  96. Naga Prasad SV, Barak LS, Rapacciuolo A, Caron MG, Rockman HA: Agonist-dependent recruitment of phosphoinositide 3-kinase to the membrane by beta-adrenergic receptor kinase 1. A role in receptor sequestration. J Biol Chem 2001, 276:18953–18959.

    PubMed  CAS  Google Scholar 

  97. Premont RT, Claing A, Vitale N, Freeman JL, Pitcher JA, Patton WA, Moss J, Vaughan M, Lefkowitz RJ: Beta2-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein. Proc Natl Acad Sci U S A 1998, 95:14082–14087.

    PubMed Central  PubMed  CAS  Google Scholar 

  98. Fusco A, Santulli G, Sorriento D, Cipolletta E, Garbi C, Dorn GW 2nd, Trimarco B, Feliciello A, Iaccarino G: Mitochondrial localization unveils a novel role for GRK2 in organelle biogenesis. Cell Signal 2012, 24:468–475.

    PubMed Central  PubMed  CAS  Google Scholar 

  99. Luo J, Benovic JL: G protein-coupled receptor kinase interaction with Hsp90 mediates kinase maturation. J Biol Chem 2003, 278:50908–50914.

    PubMed  CAS  Google Scholar 

  100. Chen M, Sato PY, Chuprun JK, Peroutka RJ, Otis NJ, Ibetti J, Pan S, Sheu SS, Gao E, Koch WJ: Prodeath signaling of G protein-coupled receptor kinase 2 in cardiac myocytes after ischemic stress occurs via extracellular signal-regulated kinase-dependent heat shock protein 90-mediated mitochondrial targeting. Circ Res 2013, 112:1121–1134.

    PubMed  CAS  PubMed Central  Google Scholar 

  101. Obrenovich ME, Palacios HH, Gasimov E, Leszek J, Aliev G: The GRK2 overexpression is a primary hallmark of mitochondrial lesions during early alzheimer disease. Cardiovascular Psychiatry and Neurology 2009, 2009:327360.

    PubMed Central  PubMed  Google Scholar 

  102. Carman CV, Som T, Kim CM, Benovic JL: Binding and phosphorylation of tubulin by G protein-coupled receptor Kinases. J Biol Chem 1998, 273:20308–20316.

    PubMed  CAS  Google Scholar 

  103. Pitcher JA, Hall RA, Daaka Y, Zhang J, Ferguson SS, Hester S, Miller S, Caron MG, Lefkowitz RJ, Barak LS: The G protein-coupled receptor Kinase 2 is a microtubule-associated protein Kinase that phosphorylates tubulin. J Biol Chem 1998, 273:12316–12324.

    PubMed  CAS  Google Scholar 

  104. Haga K, Ogawa H, Haga T, Murofushi H: GTP-binding-protein-coupled receptor kinase 2 (GRK2) binds and phosphorylates tubulin. Eur J Biochem 1998, 255:363–368.

    PubMed  CAS  Google Scholar 

  105. Whalen EJ, Foster MW, Matsumoto A, Ozawa K, Violin JD, Que LG, Nelson CD, Benhar M, Keys JR, Rockman HA, Koch WJ, Daaka Y, Lefkowitz RJ, Stamler JS: Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2. Cell 2007, 129:511–522.

    PubMed  CAS  Google Scholar 

  106. Chen X, Zhu H, Yuan M, Fu J, Zhou Y, Ma L: G-protein-coupled receptor kinase 5 phosphorylates p53 and inhibits DNA damage-induced apoptosis. J Biol Chem 2010, 285:12823–12830.

    PubMed Central  PubMed  CAS  Google Scholar 

  107. Rivas V, Carmona R, Munoz-Chapuli R, Mendiola M, Nogues L, Reglero C, Miguel-Martin M, Garcia-Escudero R, Dorn GW 2nd, Hardisson D, Mayor F Jr, Penela P: Developmental and tumoral vascularization is regulated by G protein-coupled receptor kinase 2. J Clin Invest 2013, 123:4714–4730.

    PubMed Central  PubMed  CAS  Google Scholar 

  108. Burkhalter MD, Fralish GB, Premont RT, Caron MG, Philipp M: Grk5l controls heart development by limiting mTOR signaling during symmetry breaking. Cell Rep 2013, 4:625–632.

    PubMed Central  PubMed  CAS  Google Scholar 

  109. Shukla AK, Xiao K, Lefkowitz RJ: Emerging paradigms of beta-arrestin-dependent seven transmembrane receptor signaling. Trends Biochem Sci 2011, 36:457–469.

    PubMed Central  PubMed  CAS  Google Scholar 

  110. Ungerer M, Bohm M, Elce JS, Erdmann E, Lohse MJ: Altered expression of beta-adrenergic receptor kinase and beta 1-adrenergic receptors in the failing human heart. Circulation 1993, 87:454–463.

    PubMed  CAS  Google Scholar 

  111. Bychkov ER, Ahmed MR, Gurevich VV, Benovic JL, Gurevich EV: Reduced expression of G protein-coupled receptor kinases in schizophrenia but not in schizoaffective disorder. Neurobiol Dis 2011, 44:248–258.

    PubMed Central  PubMed  CAS  Google Scholar 

  112. Grange-Midroit M: Regulation of GRK 2 and 6, β-arrestin-2 and associated proteins in the prefrontal cortex of drug-free and antidepressant drug-treated subjects with major depression. Mol Brain Res 2003, 111:31–41.

    PubMed  CAS  Google Scholar 

  113. White DC, Hata JA, Shah AS, Glower DD, Lefkowitz RJ, Koch WJ: Preservation of myocardial beta-adrenergic receptor signaling delays the development of heart failure after myocardial infarction. Proc Natl Acad Sci U S A 2000, 97:5428–5433.

    PubMed Central  PubMed  CAS  Google Scholar 

  114. Shah AS, White DC, Emani S, Kypson AP, Lilly RE, Wilson K, Glower DD, Lefkowitz RJ, Koch WJ: In vivo ventricular gene delivery of a -adrenergic receptor Kinase inhibitor to the failing heart reverses cardiac dysfunction. Circulation 2001, 103:1311–1316.

    PubMed  CAS  Google Scholar 

  115. Rengo G, Lymperopoulos A, Zincarelli C, Donniacuo M, Soltys S, Rabinowitz JE, Koch WJ: Myocardial adeno-associated virus serotype 6-betaARKct gene therapy improves cardiac function and normalizes the neurohormonal axis in chronic heart failure. Circulation 2009, 119:89–98.

    PubMed Central  PubMed  CAS  Google Scholar 

  116. Rengo G, Lymperopoulos A, Leosco D, Koch WJ: GRK2 as a novel gene therapy target in heart failure. J Mol Cell Cardiol 2011, 50:785–792.

    PubMed Central  PubMed  CAS  Google Scholar 

  117. Carotenuto A, Cipolletta E, Gomez-Monterrey I, Sala M, Vernieri E, Limatola A, Bertamino A, Musella S, Sorriento D, Grieco P, Trimarco B, Novellino E, Iaccarino G, Campiglia P: Design, synthesis and efficacy of novel G protein-coupled receptor kinase 2 inhibitors. Eur J Med Chem 2013, 69:384–392.

    PubMed  CAS  Google Scholar 

  118. Thal DM, Homan KT, Chen J, Wu EK, Hinkle PM, Huang ZM, Chuprun JK, Song J, Gao E, Cheung JY, Sklar LA, Koch WJ, Tesmer JJ: Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility. ACS Chem Biol 2012, 7:1830–1839.

    PubMed Central  PubMed  CAS  Google Scholar 

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Acknowledgements

This study was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to MN and HK); and from Grant-in-Aid for JSPS Fellows (KW).

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Correspondence to Hitoshi Kurose.

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KW wrote a draft, and MN and HK edited it. All authors read and approved the final manuscript.

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Watari, K., Nakaya, M. & Kurose, H. Multiple functions of G protein-coupled receptor kinases. J Mol Signal 9, 1 (2014). https://doi.org/10.1186/1750-2187-9-1

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