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G Protein-Coupled Receptor Regulation in Cardiovascular Disease: Role of G Protein-Coupled Receptor Kinases

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Asma S. Alonazi, Anfal F. Bin Dayel, Tahani K. Alshammari and Nouf M. Alrasheed

Submitted: 24 April 2022 Reviewed: 13 May 2022 Published: 18 June 2022

DOI: 10.5772/intechopen.105403

Novel Pathogenesis and Treatments for Cardiovascular Disease IntechOpen
Novel Pathogenesis and Treatments for Cardiovascular Disease Edited by David Gaze

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Novel Pathogenesis and Treatments for Cardiovascular Disease

Edited by David C. Gaze

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Abstract

G protein-coupled receptor kinases (GRKs), the negative regulators of G protein-coupled receptors (GPCRs), have a key role in cardiovascular disease pathophysiology. Alteration in GRKs’ expressions and/or kinase activity has been reported in preclinical animal models as well as in patients with cardiovascular diseases. This alteration might be a contributing factor to disease progression by a variety of mechanisms such as non-canonical transduction pathways. The current chapter is aimed to expand our knowledge and understanding of the function of GRKs in cardiovascular diseases, highlight their involvement, and illustrate the possible mechanistic role of GRKs in hypertensive vascular diseases and cardiac myopathy. The current chapter also is endeavoured to identify the potential molecular mechanisms by which GRKs participate in cardiovascular disease progression. Building the basics knowledge about GRKs in cardiovascular diseases will help to assess the potential utilization of GRKs as therapeutic targets and to examine the possible approaches to modulate their protein expression or to inhibit their kinase activity to prevent or attenuate cardiovascular disease progression.

Keywords

  • GRK2
  • GRK5
  • GPCR regulation
  • cardiovascular diseases
  • heart failure
  • hypertension
  • myocardial infarction

1. Introduction

Cardiovascular diseases consider as one of the major causes of death, contributing to approximately 30% of all deaths globally. In Kingdom of Saudi Arabia, approximately 37% deaths are caused by cardiovascular diseases [1]. Elevated cardiovascular disease-related morbidity and mortality result from a complex pathophysiological process including activation of many signaling transduction pathways, resulting in modification in cardiac/vascular structure, remodeling, and ultimately alteration in the functionality, which contributes to disease progression. Of importance, G protein-coupled receptors (GPCR) play a key fundamental role in various transductions signaling that participate in cardiovascular diseases pathophysiological progression. GPCRs are a superfamily of heptahelical integral membrane proteins, which respond to various stimuli. They are responsible for transduction of a plethora of signaling networks that involve in physiological and pathological actions in cardiovascular system [2, 3]. The activation of α-adrenergic, β-adrenergic, muscarinic, angiotensin II type 1 receptor (AT1) and endothelin (ETA) receptors are involved in cardiac contractility, vascular resistance, vascular and cardiac remodeling. In addition, the effect of neurohumoral systems on cardiac contractility and blood vessel tone mainly transmit their signals via corresponding GPCR. These types of receptors and their downstream transduction systems are targets of various drugs used in the treatment of cardiovascular diseases [4].

In case of hypertension, GPCRs play fundamental function in blood vessel diameter, which is mainly controlled by either contraction or relaxation of vascular smooth muscle cells. During contraction, GPCR mediated phosphorylation of contractile proteins [5]. Vasoactive peptides such as noradrenaline, angiotensin II, endothelin 1, and vasopressin activated their corresponding Gαq coupled GPCR, results in stimulation of phospholipase C-β, resulting in the formation of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 binds to their corresponding receptors which is inositol trisphosphate receptors (IP3Rs) in the sarcoplasmic reticulum; the intracellular Ca2+ store. Activation of IP3Rs resulting in efflux of Ca2+ into the cytoplasm. On other hand, DAG activates protein kinase C (PKC), promoting Ca2+ influx via enhancing the vascular channels activity such as voltage-dependent L-type Ca2+ channels. Elevated intracellular Ca2+ concentration [Ca2+]i binds to calmodulin, creating Ca2+-calmodulin complex which activate MLC kinase (MLCK) followed by phosphorylation of contractile proteins that promote myosin-actin filament interactions and consequently smooth muscle contraction [6, 7, 8, 9, 10, 11]. Contraction of vascular smooth muscle cells could persist via regulation of MLC phosphatase (MLCP). Vasoactive peptides also regulate the dephosphorylation of MLC phosphatase via different mechanisms. They utilize the PLC-DAG-PKC pathway, which in turn inhibits phosphatase activity and thus stimulates persistent contraction [12]. In addition, they activate RhoA-Rho kinase pathway, which phosphorylates MLCP and inhibits its activity [13, 14]. On the other hand, a low [Ca2+]i concentration and increased activity of MLC phosphatase promoting vascular smooth muscle cell relaxation [15]. Gαs-coupled GPCR mediated blood vessel relaxation. Adrenaline, as vasodilator, acts on corresponding receptors, recruiting Gαs to stimulate adenylyl cyclase (AC), leading to the formation of cAMP and then activation of protein kinase A (PKA). PKA plays important role in decreasing [Ca2+]i concentrations via phosphorylation of MLCK. This results in activation of calcium pumps in the plasma membrane and sarcoplasmic reticulum. Furthermore, promotes cell hyperpolarization by opening K+ channels promoting relaxation of vascular smooth muscle cells [8, 16, 17].

In case of heart failure, GPCR such as β-adrenergic receptors plays an essential role in cardiac function and in cardiac myocytes contractility. β1-adrenergic receptors couple to Gαs that activates adenylate cyclase (AC) and enhances cAMP mediate protein kinase A (PKA) activation which regulates different intracellular, sarcolemma, and myofibrillar substrates, mediating positive inotropic and chronotropic effects [18]. Gβγ subunits also activate downstream effectors that participate in cardiac transduction pathways. Moreover, it has been reported that overexpression of β1-adrenergic receptors triggers early myocytes hypertrophy and interstitial fibrosis followed by marked cardiac dysfunction in mice [18]. In addition, β1-adrenergic receptors activate various downstream signaling participating in cardiac pathophysiological processes such as cardiac hypertrophy, which might progress to heart failure development [19, 20, 21]. β2-adrenergic receptors can couple to a dual Gαs/Gαi subunits, it has been implicated in differential β2-adrenergic receptors mediated signaling such as in myocyte apoptosis [22]. Therefore, β-adrenoceptor blockers are one of the standard pharmacotherapeutics agents used in the treatment of heart failure patients [23]. β-blockers also have been shown to reduce disease progression, mortality, and morbidity in patients with heart failure with reduced ejection fraction (HFrEF) [24]. This effect appears primarily related to the ability of β-adrenoceptor blockers to protect the heart from the harmful effects of receptor over-stimulation [25].

As the effect of neurohumoral systems on cardiovascular system mainly transmits their signals via GPCRs, understanding of the GPCR regulation and their G-protein dependent/independent signaling reveals a novel therapeutic approach that could attenuate cardiovascular-related complications. In current chapter, we provide insight into the potential effect of GPCR negative regulators, focusing particularly on G protein-coupled receptor kinases (GRKs) and their possible effect on cardiovascular diseases.

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2. GPCRs regulations

Repeated or prolonged/continues agonist stimulation of GPCRs resulted in loss of receptor response characterized as receptor desensitization. It can be described as physical uncoupling of G proteins from their associate receptors subsequent in diminish their ability to initiate intracellular signaling cascades [26]. As shown in Figure 1, receptor desensitization process is initiated by receptor phosphorylation. It can be mediated by G protein-coupled receptor kinases (GRKs), which phosphorylate agonist-bound active receptor inducing homologous type of receptor desensitization [27]. Receptor phosphorylation can be also mediated by second messenger kinases such as PKA and PKC, which can phosphorylate receptors regardless of whether the GPCR is occupied by agonist or not, thus producing heterologous type of receptor desensitization [27, 28, 29]. Receptor phosphorylation subsequently increases the affinity of the receptors for β-arrestins proteins binding, consequently prevents further receptors-G protein interactions and therefore termination of G protein-related signaling [30]. Accordingly, the phosphorylated GPCR/β-arrestin complex is subjected for clathrin-mediated endocytosis, followed by either recycling, or degradation [31, 32, 33]. Importantly, β-arrestins function as ligand-regulated adaptor scaffolds that enable the transduction of signaling pathways in non-canonical manner [34].

Figure 1.

GPCR desensitization and related signaling transductions pathways. GPCR desensitization by GRKs and β-arrestins process initiated with ligand binding, receptor activation and dissociation of G protein. Consequently, GRKs phosphorylate agonist-occupied GPCRs (activated receptors) at third intracellular loop or C-terminal. Receptor phosphorylation resulting in enhances the affinity for β-arrestin recruitment then binding to the receptors causing termination of G-protein dependent transduction signaling and receptor desensitization. After that, the receptors undergo internalization and initiation of G protein-independent transduction signaling.

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3. G protein-coupled receptors kinases (GRKs)

G Protein-Coupled Receptors Kinases (GRKs) are family of seven members of serine/threonine kinases [35]. They are allocated into three subcategories: the first category is visual GRKs including GRK1 and GRK7; the second and third categories are non-visual GRKs including β-adrenergic receptor kinase subcategory, containing GRK2 (β-ARK1) and GRK3 (β-ARK2) and; the GRK4 subcategory, containing GRK4, GRK5, and GRK6 [27]. Regarding GRKs tissue distribution, GRK1 and GRK7 are primarily expressed in the retina mediating photoreceptor regulation. GRK2, GRK3, GRK5, and GRK6 are ubiquitously expressed in various tissues; however, GRK4 is limitedly distributed to testes, kidneys, and some areas of the brain. Hence, GRK2, GRK3, GRK5, or GRK6 is the potential regulator for the majority of GPCRs [36, 37, 38].

In cardiovascular system, the distribution pattern and expression levels of GRK are crucial factors contributing to their functionality in various cell types. Previous reports show that GRK2, GRK3, and GRK5 are highly expressed in the human heart [39]. GRK isoforms distribution is different among various heart cells. GRK2 and GRK5 are expressed in almost all cardiac cells, while GRK3 distribution is limited to cardiac myocytes [4, 40]. GRK2 is expressed in the vascular endothelium, arterial smooth muscle, and in the myocardium. GRK2 is also expressed in the kidney, especially in the renal proximal tubule [41].

The structure of GRKs comprises of three domains: N-terminal; an amino terminal domain, central serine/threonine protein kinase/catalytic domain, and C-terminal; a carboxyl terminal domain. The N-terminal domain is implicated in receptor recognition. It includes a region of a regulator of G protein signaling (RGS) homology domain (RH) [31, 35]. In GRK2, Gβγ binding site has been mapped in the N-terminal region causing binding of GRK2 to cell membrane [42]. The central domain is a serine/threonine protein that exerts the kinase catalytic function in all GRKs. The C-terminal domain structure is different among GRKs subfamilies. It is implicated in GRK membrane localization. For instant, GRK5 is located at cell membrane level as the C-terminus of GRK5 contains lipid-binding sites that interact with the phospholipid in the cell membrane. On other hand, GRK2 and GRK3 are cytoplasmic proteins that are recruited to the plasma membrane upon agonist binding and receptor activation. Their C-terminal domains contain pleckstrin homology (PH) domain, which comprises binding sites for the cell membrane phospholipid (PIP2) and Gβγ subunits [26, 35, 43]. As a multi-domain protein, GRK acts as a negative GPCR signaling regulator, terminating G protein-dependent signaling and initiating other G protein-independent signaling pathways [30, 44]. For instance, reported evidence reported that GRK functions are expanded more than receptors phosphorylation. GRKs are able to interact with various cellular proteins mediating non-canonical GPCR signaling [31, 45]. Of importance, GRK expression and activity are changed in many cardiovascular diseases such as in case of hypertension or heart failure. Thus, better understanding of the diseases associated with alteration in GRKs’ expression as well as their functional roles in cardiovascular system is fundamental to develop a new therapeutic target.

3.1 GRKs in hypertension

In hypertension, continuous activation of Gαq coupled receptors such as ETA and AT1 mediate vascular smooth muscle contraction and enhance peripheral vascular resistance [46]. Current evidence shows that GRK2 plays an important function in regulation of prolonged Gαq-related signaling in vascular smooth muscle cells and consider as the main negative regulator of vasoactive peptide corresponding GPCRs. Moreover, previously published studies reported that GRK2 negatively regulate ETA and P2Y2 receptors in aortic smooth muscle cells [47, 48]. Reported evidence shows that inhibition of GRK2 kinase activity diminishes the desensitization process of AngII/AT1 and UTP/P2Y2 induced arterial smooth muscle contractions [49]. Indeed, published studies show that GRK2 expression is augmented in hypertension, in both hypertensive animal models and hypertensive patients [50, 51, 52, 53, 54, 55]. Therefore, enhanced GRK2 expression may possibly participate in the pathophysiology of hypertension development. For instant, GRK2 has been reported to attenuate endothelial NO production [56]. Furthermore, GRK2 is reported to mediate the desensitization of β-adrenoceptors, which mediates vasodilation. Thus, enhanced GRK2 expressions may impair vasodilation in hypertension, which possibly contributes to enhancing vascular tone and elevation of blood pressure [53]. Additionally, it has been reported that GRK2 overexpression in vascular smooth muscle cells resulted in a 30% increase in vascular wall thickness [52], suggesting a possible link between GRK2 over-expression in hypertension and hypertension-induced vascular remodeling [57]. Recently published paper show that elevated GRK2 expression hypertension has a potential to promote vascular smooth muscle growth and proliferation possibly via PI3K-Akt signaling, followed by release the GSK3-mediated inhibition of cell cycling progression, therefore aggravate hypertensive induced pathophysiological vascular remodeling [58].

Still, it is not clear if the changes in GRK2 expression are a contributing factor for hypertension development or a consequence of hypertension, which needs further investigation. Moreover, further investigations are required to understand the molecular mechanisms underlying these changes and how the alterations in GRK expression implicated in triggering or progression of hypertension might contribute to the development of novel diagnostic and/or therapeutic strategies to control hypertension or prevent its complications.

3.2 GRKs in heart failure

Myocardial GRK2 and GRK5 have been shown to be involved in the pathophysiology of heart failure [40]. Indeed, several evidences highlight GRK2 as well as GRK5 as the key regulators of β-adrenoceptor [59, 60]. Of importance, recently published paper describes that GRK2 and GRK5 are new therapeutic targets for pathological cardiac hypertrophy and may attenuate morbidity and mortality rates [61]. Dysregulation of β-adrenoceptor is a pathological characteristic of heart failure; in particular, the receptors are considerably downregulated and desensitized as a result of the upregulated levels of GRK2 and GRK5 [16]. Enhanced expression and activity of GRK2 are associated with the loss of β-adrenoceptor functions that induces deleterious effects in the heart functionality contribute to progression of heart failure [62]. Overstimulation of β-adrenoceptor as a subsequent of continuous sympathetic activation, resulting in GRK and β-arrestins induced desensitization and downregulation of β-adrenoceptor [63]. Initially, this process is adaptive response to overcome receptor overactivation. However, prolonged excessive stimulation mediated receptor downregulation has been reported inducing harmful effect to the heart and consequently heart failure development [63, 64]. Notably, alterations in GRKs have been observed in heart failure [39, 65, 66]. Indeed, several evidences highlight GRK2 as well as GRK5 as the key regulators of β-adrenoceptor [59, 60]. Several reported evidence have shown that GRK2 expression and activity are significantly increased in the failing heart [39, 67, 68]. Enhanced GRK2 expression and altered functionality have been found in heart failure status [39, 65, 66, 69]. Moreover, up-regulation of GRK2 level was detected in end-stage dilated heart failure patient [65]. Even though the mechanism of β-adrenoceptor overstimulation mediated GRK2 upregulation is not clearly understood, published reports show that GRK2 dysfunction plays an essential function in the pathophysiology of heart failure [70] suggesting that alteration in GRK2 function participates in heart failure pathology. Altered GRK2 expression or activity appears to contribute to disease progression through various molecular mechanisms. Therefore, targeting GRK2 expression or inhibition of its activity has been suggested as a therapeutics strategy for treatment of heart failure patients [71, 72].

Reported evidence shows that overexpression of a peptide inhibitor of GRK2; carboxy terminal domain (βARKct) which lacks to membrane translocation function inhibits GRK2 activity and prevents desensitization of the receptors resulting in restoring of β-adrenoceptor function and enhanced cardiac contractility in experimental animals of heart failure [73, 74, 75]. Moreover, Gβγ-GRK2 inhibition reduces pathological effect of myofibroblast activation. Thus, Gβγ-GRK2 inhibition might be a potential therapeutic strategy to attenuate pathological myofibroblast activation, interstitial fibrosis, cardiac remodeling, and progression of heart failure [76].

It has been reported that cardiac dysfunction could be attenuated by inhibition of GRK2 activity [62]. Interestingly, it has been reported that paroxetine, selective serotonin re-uptake inhibitor (SSRI) approved by FDA for treatment of depression, significantly inhibited GRK2 kinase activity [49, 77, 78]. Published studies showed capability paroxetine as GRK2 inhibitor in reversing cardiac remodeling in experimental models of acute myocardial infarction [79, 80]. Therefore, paroxetine may perhaps be used as a therapeutic approach for targeting GRK2 catalytic activity and potentially provide a protective role against cardiac hypertrophy development via its function as GRK2 inhibitor.

GRK5 another GRK member that mediates phosphorylation and desensitization of β-adrenoceptor is well known to regulate heart functions [72]. Several studies suggest that GRK5 plays a crucial role in various cardiovascular diseases. For instance, previous studies show that GRK5 overexpressing mice developed cardiac hypertrophy, which rapidly progressed to heart failure [81]. Moreover, GRK5 knockout mice showed attenuated hypertrophic responses [82]. Furthermore, GRK5 overexpressing mice showed an alteration in myocardial performance including attenuation of contractility, cardiac output, stroke work, and stroke volume [83]. Of note, GRK5 levels were shown to be markedly elevated in heart failure patients and patients with left ventricular volume overload disorders and dilated cardiomyopathic hearts [84, 85, 86].

GRK5 overexpressed transgenic mice exhibited enhanced susceptibility to pressure overload-induced cardiac hypertrophy and cardiac dysfunction [87]. Furthermore, cardiac-specific GRK5 transgenic mice demonstrated reduced cardiac function and increased adverse cardiac remodeling in a myocardial infarction-induced heart failure mice model [64]. On other hand, heart hypertrophic responses were attenuated in GRK5 knockout mice [88], these studies demonstrated the possible functions of GRK5 in pathological cardiac remodeling development. Interestingly, several lines of evidence show that GRK5 can translocate to the nucleus, exerting its non-canonical functions. For instance, it was shown that GRK5 in the cardiomyocyte nuclei acts as a class II histone deacetylase (HDAC) kinase, phosphorylating HDAC5 and leading to de-repression of myocyte enhancer factor 2 (MEF2)-mediated hypertrophic gene transcription [81, 89]. In addition, it was demonstrated that GRK5 interacts with hypertrophic transcription factors like nuclear factor of activated T cell (NFAT) and nuclear factor κ-B (NF-κB) [81, 87, 90, 91]. These studies indicate that GRK5 has a major role in the pathogenesis of the cardiovascular disorders and GRK5 might be a therapeutic target for heart failure. Recently, it has been demonstrated that KR-39038, a novel small molecule inhibitor of GRK5, significantly inhibited cellular hypertrophy and HDAC5 phosphorylation in neonatal rat ventricular myocytes. This inhibitor was able to minimize the left ventricular weight, improve cardiac function and ameliorate myocardial remodeling in animal model of heart failure [92]. Another important agent proposed as a GRK5 inhibitor is an anti-inflammatory and anti-allergic immunomodulator, named amlexanox [93]. This agent was able to inhibit GRK5 induced MEF2 activation in neonatal rat ventricular myocytes and inhibit GRK5 mediated HDAC5 phosphorylation in cellular model of cardiac hypertrophy [93, 94].

3.3 GRKs in myocardial infarction

It has been reported that GRK2 expressions upregulated in peripheral blood lymphocytes in patients with acute ST-segment elevation myocardial infarction. Enhanced lymphocyte GRK2 expressions are associated with worse cardiac functionality. These studies indicate that GRK2 could be predictive of myocardial remodeling after myocardial infarction [95, 96]. Enhanced GRK2 levels and activity are deleterious to post-ischemic myocardium in acute ischemia/reperfusion (I/R) injury animal model [97]. It has been reported that GRK2 peptide inhibitor; βARKct provides cardioprotective effect, which modulate GRK2-mediated PI3K-Akt-NOS signaling pathway in the ischemic heart which validates GRK2-related effect on survival and apoptotic signaling in the ischemic heart [97]. βARKct expression mediated GRK2 inhibition modulate Akt downstream pro-survival signaling such as reduced Caspase-3 activity, increased eNOS activation and NO production and then reduced apoptosis and cell death [97]. Furthermore, decreasing GRK2 expression in cardiomyocytes attenuate myocyte apoptosis possibly via Akt/Bcl-2 mediated mitochondrial protection and limits I/R- provoked injury and improves post-ischemia recovery in the heart [98]. Additionally, it has been reported that fibroblast specific GRK2 knockout has a protective effect after myocardial I/R injury in mice. GRK2 fibroblast knockout mice decreased the infarct size, increased ejection fraction, preserved cardiac function, and also reduced tumor necrosis factor-α expression, fibrotic gene expression, and fibrosis development [99].

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4. Conclusions

Cardiovascular diseases are a leading cause of death worldwide. The pathophysiological mechanisms are regulated by a GPCR mediated complex network of transduction pathways. The functions of GRKs, negative regulators of GPCR, are not limited to receptors desensitization. It is expanded further to activations of many transductions in non-classical manner. As the expression and kinase activity of GRK2 and GRK5 are altered in cardiovascular diseases, Therefore, better knowledge of the transduction events which mediated by up-regulated GRK2 and/or GRK5 in terms of the expression, activity, and localization would help to develop a novel strategy for targeting their expressions or inhibiting activity. This will participate in building a knowledge-based platform identifying a new therapeutic target to prevent the progression of cardiovascular diseases. Many different approaches could be applied, including small molecule inhibitors, gene therapy, and the use of advanced drug delivery systems to potentially prevent the progression of cardiovascular disease. Overall, GRKs play an important role in cardiovascular diseases progression. Pharmacological intervention of GRK5 as well as GRK2 would provide a novel possible future target for cardiovascular disease progression prevention.

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Acknowledgments

The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia for funding this research work through project no. (IFKSUDR_H150).

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Conflict of interest

The authors declare no conflict of interest.

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Written By

Asma S. Alonazi, Anfal F. Bin Dayel, Tahani K. Alshammari and Nouf M. Alrasheed

Submitted: 24 April 2022 Reviewed: 13 May 2022 Published: 18 June 2022

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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