**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**–**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.

*DOI: http://dx.doi.org/10.5772/intechopen.105403 G Protein-Coupled Receptor Regulation in Cardiovascular Disease: Role of G Protein-Coupled…*

#### **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 [50–55]. 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 overexpression 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.
