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• W2473533692 abstract "HomeJournal of the American Heart AssociationVol. 5, No. 7G Protein–Coupled Receptor Kinases: Crucial Regulators of Blood Pressure Open AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citations ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessReview ArticlePDF/EPUBG Protein–Coupled Receptor Kinases: Crucial Regulators of Blood Pressure Jian Yang, MD, PhD, Van Anthony M. Villar, MD, PhD, Ines Armando, PhD, Pedro A. Jose, MD, PhD and Chunyu Zeng, MD, PhD Jian YangJian Yang Department of Nutrition, Daping Hospital, The Third Military Medical University, Chongqing, China Department of Cardiology, Chongqing Key Laboratory for Hypertension, Chongqing Institute of Cardiology, Chongqing Cardiovascular Clinical Research Center, Daping Hospital, The Third Military Medical University, Chongqing, China Search for more papers by this author , Van Anthony M. VillarVan Anthony M. Villar Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC Search for more papers by this author , Ines ArmandoInes Armando Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC Search for more papers by this author , Pedro A. JosePedro A. Jose Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC Search for more papers by this author and Chunyu ZengChunyu Zeng Department of Cardiology, Chongqing Key Laboratory for Hypertension, Chongqing Institute of Cardiology, Chongqing Cardiovascular Clinical Research Center, Daping Hospital, The Third Military Medical University, Chongqing, China Search for more papers by this author Originally published7 Jul 2016https://doi.org/10.1161/JAHA.116.003519Journal of the American Heart Association. 2016;5:e003519IntroductionHypertension, a complex trait determined by genetic, epigenetic, and environmental factors and their intricate interaction, is an important public health challenge worldwide because of its high prevalence and concomitant increase in the risk for cardiovascular disease. Unfortunately, the prevalence of hypertension is increasing in both developed and developing countries.1 As a consequence of the increase in global prevalence, the total number of adults with hypertension is predicted to increase to 1.56 billion in 2025.2 This prospect is daunting, given that, in 2010, high blood pressure was already the biggest single contributor to global mortality and disease burden.The pathogenesis of essential hypertension is complex. Many organs and systems including kidneys, arteries, microcirculation, heart, immune system, nervous system, and endocrine factors are involved in the pathophysiology of hypertension. Among them, kidneys and arteries are major contributors to the development of hypertension.3, 4 Various agonists binding to plasma membrane receptors regulate renal sodium transport and fluid balance and maintain the equilibrium between vasoconstriction and vasodilation. Many of these agonists transmit their “information” via G protein–coupled receptors (GPCRs). GPCRs mediate cellular responses to diverse extracellular stimuli and play a vital role in the control of physiology and behavior.5 GPCR kinases (GRKs) interact with the agonist‐activated GPCRs to promote receptor phosphorylation and to initiate receptor desensitization.6 The wide variety of GPCRs that are responsible for optimal blood pressure control7 leaves no doubt that GRKs play a vital role in the regulation of blood pressure. A number of studies have shown that GRKs are associated with hypertension, blood pressure response to antihypertensive medicines, and adverse cardiovascular outcomes of antihypertensive treatment.8, 9, 10, 11 In this paper, we reviewed our evolving understanding of the role of GRKs in hypertension, summarized the current knowledge of GRK‐mediated regulatory mechanisms, and highlighted the potential for targeting GRKs in the treatment of hypertension. This information may advance our understanding of the role of GRKs in the control of blood pressure and provide novel insights into the field of translational medicine, especially regarding the design of new therapeutic approaches for the treatment of hypertension.Abnormal GPCR Function and HypertensionGPCRs, the largest and most functionally diverse superfamily of cell‐surface receptors, share a common architecture consisting of 7 transmembrane domains connected by extracellular and intracellular loops.5 Upon stimulation, GPCRs interact with heterotrimeric G proteins that in turn dissociate into 2 functional units, namely, Gα and Gβγ subunits, both of which stimulate the activation of downstream proteins (Figure 1). In the vasculature, some GPCRs mediate vasoconstriction and/or vascular remodeling, such as angiotensin II (Ang II) type 1 receptor (AT1R), α‐adrenergic receptor (α‐AR), endothelin A receptor, and neuropeptide Y receptor, whereas other GPCRs induce vasodilatation and/or inhibition of vascular remodeling, including the acetylcholine receptor, β‐AR, the endothelin B receptor, and the dopamine receptor, among others. Similar to some renal tubular receptors (e.g., dopamine receptor, atrial natriuretic peptide receptor, AT2R, Mas receptor, and endothelin B receptor) decrease renal sodium reabsorption, whereas others including the AT1R, insulin receptor, and mineralocorticoid receptor increase renal sodium reabsorption. The balance between pro‐ and antihypertensive receptor activity is important to keep the blood pressure in the normal range. Abnormal GPCR functions lead to increased blood pressure; for example, increased AT1R function and impaired dopamine receptor function are found in hypertensive patients and hypertensive animal models.12, 13 The causes of abnormal GPCR function are complex and may include perturbation of DNA modification, receptor expression, and phosphorylation.14, 15 Among these modifications, GPCR phosphorylation is important. In hypertensive states, for example, dopamine D1 receptor (D1R) is hyperphosphorylated, which leads to uncoupling of the dopamine receptor from its GαS/effector protein complex and impairment of dopamine‐mediated natriuresis and vasodilation.13, 15, 16 It is known that the state of phosphorylation of GPCRs is modified by 2 kinds of enzymes. Kinases (e.g., GRKs) increase GPCR phosphorylation, whereas phosphatases (e.g., protein phosphatase 2A) bring about GPCR dephosphorylation. Renal protein phosphatase 2A activity is decreased in adult spontaneously hypertensive rats (SHRs) but increased in young (aged 2 weeks) SHRs, whereas GRK4 activity is markedly increased in hypertension.16, 17, 18 Nevertheless, the GRKs have received, by far, the most attention in abnormal GPCR phosphorylation in renal tubules in hypertension.Download PowerPointFigure 1. Schematic representation of the process of GPCR desensitization. On binding to their cognate ligands, GPCR activation initiates dissociation of cognate trimeric G protein, promoting GPCR phosphorylation by GRKs, leading to receptor association with members of the arrestin family, which inhibits further G protein activation. AC indicates adenylyl cyclase; GDP, Guanosine‐5′‐diphosphate; GIRK, G protein–gated inwardly rectifying potassium channel; GPCR, G protein–coupled receptor; GRK, G protein–coupled receptor kinase; GTP, Guanosine‐5′‐triphosphate; MEKs, mitogen‐activated protein/extracellular signal‐regulated protein kinase kinases; P, phosphorylation; PI3K, phosphatidylinositol‐3 kinase; PKA, protein kinase A.Role of GRKs in the Regulation of Blood PressureGRK Family MembersAlthough there are >800 known GPCRs in the human genome, it is surprising that only 7 GRKs (GRK1–7) have been identified. The GRKs constitute a family of 7 serine/threonine protein kinases characterized by their ability to specifically recognize and phosphorylate agonist‐activated GPCRs. Based on divergent C‐terminal domain architecture and membrane‐targeting mechanisms, the GRKs are classified into 3 subfamilies: (1) the GRK1 subfamily, also known as the opsin kinase family, consisting of the rhodopsin kinase GRK1 and visual pigment kinase GRK7; (2) the GRK2‐like subfamily, also known as the β‐AR kinase family, consisting of GRK2 (β‐AR kinase 1) and GRK3 (β‐AR kinase 2); and (3) the GRK4‐like subfamily, consisting of GRK4, GRK5, and GRK6.6 All GRKs possess similar structural organization with an N‐terminal domain (≈185 amino acids), a catalytic domain (≈270 amino acids), and a C‐terminal domain (≈105–230 amino acids) (Figure 2). The carboxy tail region is GRK subtype‐specific; it is prenylated in the GRK1 subfamily, binds to Gβγ, contains a pleckstrin homology domain in the GRK2 subfamily, and has a C‐terminal helix/palmitoylation site in the GRK4 subfamily.6 The C‐terminal domain of GRKs is the most important determinant of subcellular localization and agonist‐dependent translocation.19 There is a nuclear localization sequence in all members of the GRK4 subfamily; the nuclear localization sequence in GRK5 and GRK6, but not GRK4, binds to DNA in vitro.20Download PowerPointFigure 2. Structural domain distribution of GRKs. All GRKs possess an N‐terminal domain and a catalytic domain, both of which are followed by a Regulator of G protein signaling (RGS) homology domain, and a C‐terminal domain. GRK2 and GRK3 have another PH domain that interacts with G protein βγ subunits. The various isoforms of human GRK4 (GRK4α, GRK4β, GRK4γ, and GRK4δ) have differences in presence or in‐frame deletion of certain exons. The solid black square represents the presence of exon 2 and/or exon 15, whereas the dotted square represents the deletion of exon 2 and/or exon 15. GRK indicates G protein–coupled receptor kinase; PH, pleckstrin homology; RH, RGS homology.The distribution of GRK subtype expression is different among subtypes. GRK1, GRK4, and GRK7 are expressed in limited numbers of tissues. GRK1 and GRK7 are found almost exclusively in the retina and regulate the opsins. GRK4 is expressed in testis, myometrium, kidney, artery, and intestine.13, 15, 16, 17, 18, 21 By contrast, other GRKs (GRK2, GRK3, GRK5, and GRK6) are expressed ubiquitously throughout the body. Accordingly, except for GRK1 and GRK7, other GRK members (GRK2–6) exert different physiological effects, specifically, the regulation of blood pressure by the cardiovascular system and the kidney.8, 9, 10, 11, 16, 17, 18, 20, 21, 22, 23, 24G protein–coupled receptor kinase 2.The human GRK2 (official name ADRBK1) gene locus maps at the long arm of chromosome 11: 11q13.2 by Ensembl, 11q13.1 by Entrez Gene (National Center for Biotechnology Information), and 11q13 by the HUGO Gene Nomenclature Committee (HGNC). Human GRK2 cDNA encodes a protein of 689 amino acids (79.573 kDa) with an overall 98.0% amino acid and 92.5% nucleotide identity with bovine GRK2. The 23‐kb human GRK2 gene consists of 21 exons interrupted by 20 introns, with a predicted transcription start site ≈246 bases upstream of the start ATG. The human GRK2 gene has 12 highly conserved catalytic region subdomains in which 5 are encoded entirely within exons, specifically, exons 8, 9, 10, 11, and 12. Exons bounded by introns range in size from 52 (exon 7) to 163 bases (exon 18). The 2 largest exons represent the 5′‐flanking region (359 bases, including 113 bases of coding sequence) and the 3′‐coding plus noncoding region of the gene (>1200 bases). Sequence analysis of the 5′‐flanking/promoter region reveals many features characteristic of mammalian housekeeping genes, namely, the lack of a TATA box, an absent or nonstandardly positioned CAAT box, high GC content, and the presence of Sp1‐binding sites. The conserved region of the C‐terminal domain is important for enzyme–receptor interaction required for GRK2 to catalyze receptor phosphorylation.25 In addition, a Gβγ binding site of GRK2 is also localized in the C‐terminal pleckstrin homology domain. Phosphorylated Raf kinase inhibitory protein binds to the N terminus of GRK2, resulting in the inhibition of its function.26Distribution of GRK2.GRK2 is ubiquitously expressed in mammals. In the cardiovascular system, GRK2 is expressed in the vascular endothelium, arterial smooth muscle, and myocardium.27, 28 GRK2 is also abundant in the kidney, especially in the renal proximal tubule.29 This renal expression indicates that GRK2 plays a vital role in the regulation of ion and fluid transport and, ultimately, blood pressure. GRK2 is expressed in both cytoplasm and the cell membrane. It shuttles between the cytosol and plasma membrane, anchoring to the latter through its pleckstrin homology and Gβγ binding domains at the C‐terminus.30 The subcellular localization of GRK2 at the mitochondrial outer membrane27, 31 may indicate a role of GRK2 in regulating mitochondrial biogenesis and cellular energy production. Indeed, GRK2 increases mitochondrial superoxide production and decreases oxygen consumption and ATP production.32Regulation of GRK2 in the regulation of blood pressure.A role of GRK2 in the regulation of blood pressure has been shown in animal models with partial germline deletion, universal GRK2 knockdown, and targeted overexpression or knockdown in vascular smooth muscle and endothelial cells.22, 33, 34, 35, 36 GRK2 plays an important role in the regulation of blood pressure.7 Germline deletion of Grk2 is lethal.37 GRK2 deficiency in global adult hemizygous mice (Grk2+/−) has no effect on basal blood pressure but increases the vasodilator response to acetylcholine or isoproterenol and protects against Ang II–induced hypertension and vascular remodeling that is partially caused by increased nitric oxide bioavailability.33 Cohn et al also found in mice that inhibition of vascular smooth muscle GRK2 by either overexpression of the C‐terminal portion of GRK2 or vascular smooth muscle–specific ablation of GRK2 protein expression has no effect on blood pressure.35 This method of GRK2 silencing also had no effect on the elevated blood pressure resulting from unilateral renal artery stenosis.35 In contrast, overexpression of GRK2 in vascular smooth muscle in mice increases resting blood pressure.34 This study would agree with the report that GRK2 inhibits adiponectin function; adiponectin may be antihypertensive.38, 39 Portal hypertension caused by common bile duct ligation is also associated with an increase in GRK2 expression in the mesenteric artery.40 Consequently, deletion of GRK2 should result in a decrease in blood pressure; However, global knockdown of Grk2 expression using small hairpin interfering RNA in male mice produces hypertension that is associated with vascular remodeling caused in part by increases in cell proliferation at age 6 months but not at 3 months.22 The causes of the differences are not known, but the differential effects of GRK2 on vasoconstriction and vasodilation may explain this apparently conflicting results. In small hairpin Grk2 knockdown mice, for example, both phenylephrine‐induced contractile responses and isoproterenol‐mediated vasodilation are increased; which one dominates would eventually determine the physiological phenotype.22 After inhibition of GRK2 by either peptide inhibition or gene ablation, downregulation of GRK2 does not only increase β‐AR–mediated vasodilation but also enhances α1D‐AR–stimulated vasoconstriction and could explain the lack of effect on blood pressure of a decrease in GRK2 expression or function.35 Whether or not the discrepant results could be related to sex differences were not determined, but the small hairpin Grk2 studies were performed only in male mice because the Grk2 small hairpin RNA transgene was incorporated into the Y chromosome22; the sexes of the mice in the other studies were not given. Nevertheless, the transgenic overexpression of GRK5 in vascular smooth muscle increases blood pressure to a greater extent in male than in female mice.23 The discrepant results may also be related to the extent of downregulation of GRK2 in different tissues.GRK2 is expressed to a greater extent than GRK5 in endothelial cells.41 Increased GRK2 expression in injured endothelial cells in injured liver leads to intrahepatic portal hypertension, and knockdown of GRK2 in liver sinusoidal endothelial cells leads to an increase in portal pressure that is related to decreased endothelial nitric oxide synthase production of nitric oxide.36 Selective deletion of Grk2 in the endothelium affects the aorta's receptor‐dependent and ‐independent vasoconstriction and increases vascular inflammation and tissue degeneration by increasing mitochondrial reactive oxygen species production, which is also associated with hypertension.42 Exercise decreases blood pressure, improves insulin sensitivity, and decreases mesenteric arteriolar and myocardial GRK2 expression in SHRs.43 The effects in mesenteric arterioles were prevented by mesenteric arteriolar overexpression of GRK2. In contrast, downregulation of endothelial vascular GRK2 expression in SHRs that is initiated at the prehypertensive stage (age 4 weeks) subsequently improves vascular insulin sensitivity that helps to limit the progression of hypertension.43 GRK2 impairs insulin sensitivity by binding to the insulin receptor substrate 1 but not to the insulin receptor.44 GRK2 expression in renal preglomerular vessels increases with aging in male but not in female rats.45 GRK2 regulates the blood pressure by modulating other receptor‐mediated vascular responses, including endothelin A receptor, neurotensin receptor 1, and P2Y receptor.46, 47, 48 The reasons why knockdown of GRK2 in mice in different studies leads to different effects on blood pressure need to be elucidated.GRK2 also plays an important role in the renal regulation of sodium excretion and blood pressure. GRK2 keeps amiloride‐sensitive epithelial Na+ channels in the active state.49, 50, 51 GRK2 upregulates epithelial Na+ channel activity by a mechanism that depends not on its kinase activity but rather on the ability of the RGS homology domain of GRK2 to interact with and inhibit the α subunit of Gq/11, a negative regulator of epithelial Na+ channels.50 GRK2‐mediated phosphorylation of the C‐terminus of β–epithelial Na+ channels and phosphorylation of Nedd4‐2 prevent its ability to inhibit epithelial Na+ channel activity.51, 52 GRK2 negatively regulates neurotensin receptor 1 function; there are more neurotensin binding sites in the renal cortex than in the renal medulla, and they decrease sodium excretion, but the mechanism is not known.47 GRK2 also regulates the phosphorylation of renal D1R and D1R‐mediated natriuresis.53 In the human kidney, antisense oligonucleotides against GRK2 and GRK4 blunt the later stages of D1R desensitization; heparin, a nonselective GRK inhibitor, decreases GRK2 and GRK4 expression and attenuates the desensitization of D1R.54 Both GRK2 and GRK4 are involved in the desensitization of renal D1R in obese Zucker rats.55 Oxidative stress is involved in the regulation of GRK2 of D1R.56 Both in vivo and in vitro studies show that oxidative stress activates nuclear factor κB, causing an increase in protein kinase c (PKC) activity, which leads to GRK2 translocation and subsequent D1R serine hyperphosphorylation.56 The functional consequence of this phenomenon is the inability of D1R to inhibit Na+,K+‐ATPase activity and promote sodium excretion, which could contribute to the increase in blood pressure.56 Interestingly, we recently found that prenatal lipopolysaccharide exposure results in increased GRK2 expression, increased D1R phosphorylation, and impaired D1R‐mediated natriuresis and diuresis in the offspring. These findings suggest that a dysfunction of the renal D1R induced by abnormal GRK2 expression is also involved in fetal‐programmed hypertension.57 GRK2 is also involved in desensitization of D2R; D2R dysfunction is involved in the pathogenesis of hypertension.58, 59Role of GRK2 in spontaneous hypertension.GRK2 expression in several tissues is increased in several diseases, including spontaneous hypertension in humans and experimental animals and in animal models of diabetes and insulin resistance.28 Gros et al reported that in SHRs, GRK2 expression is increased in both lymphocytes and aortic vascular smooth muscle cells and is accompanied by impairment of β‐adrenergic–mediated stimulation of adenylyl cyclase activity and β‐AR–mediated vasodilation.60 The impairment in β‐adrenergic–mediated aortic vasodilation and increased vascular GRK2 expression are observed in SHRs aged 10 and 15 weeks but not 5 weeks. Increased aortic vascular GRK2 expression is also present in the Dahl salt‐sensitive hypertensive rats after 4 weeks of a high salt diet.60 Oliver et al also reported impaired aortic β1‐ and β2‐AR–mediated vasodilation, but not β3‐AR–mediated vasodilatation, and increased aortic expression of GRK2 in adult SHRs61; however, this group did not find such differences in the mesenteric artery of adult Wistar‐Kyoto (WKY) rats and SHRs.61 Moreover, in rats made hypertensive by L‐NAME, their aortas had increased β2‐AR–mediated vasodilation and decreased GRK2 expression; their mesenteric arteries had decreased β2‐AR‐mediated vasodilation, without changes in GRK2 expression—opposite to that found in SHRs.61 Whether or not inconsistencies are present in other models of hypertension remain to be determined.GRK2 is expressed in peripheral blood mononuclear cells and lymphocytes.7, 62 GRK activity and GRK2 expression are increased in lymphocytes of hypertensive humans and experimental models of hypertension.60, 63, 64 Lymphocyte GRK2 mRNA expression directly correlates with systolic blood pressure and plasma norepinephrine levels.64 GRK2 in lymphocytes is elevated >30% among persons with systolic blood pressure >130 mm Hg. GRK2 protein expression in lymphocytes is also increased about 2‐fold, and its activity increased >40% in African Americans, a population at higher risk for hypertension and cardiovascular complications compared with other groups.64G protein–coupled receptor kinase 3.The human GRK3 (official name ADRBK2) gene locus maps at the long arm of chromosome 22: 22q12.1 by Ensembl and Entrez Gene and 22q11 by HGNC. Similar to GRK2, the GRK3 gene also has 21 exons ranging in size from 52 to 163 bases. The amino acid sequence of human GRK3 is 84%, identical to that of human GRK2. Similarly, bovine GRK3 has 85% amino acid identity with GRK2. The most highly conserved region between GRK3 and GRK2 is the protein kinase catalytic domain, which has only 12 amino acid differences (95.0% identity), 4 of which are conservative substitutions (96.7% conservative). In contrast, the amino‐terminal domain (80.7% identity, 89.8% conservative) and carboxyl‐terminal domain (76.6% identity, 88.9% conservative) are less well conserved.GRK3 belongs to the GRK2 subfamily and is ubiquitously expressed in the body; however, unlike GRK2 and GRK5, GRK3 is not expressed in endothelial cells.41 In contrast, in cardiac myocytes, the GRK2 subfamily expression is GRK5 to GRK3 to GRK2. Many studies have focused on the role of GRK2 and GRK3 on cardiac function.8, 65 GRK3 and GRK2, however, have distinct roles in receptor selectivity in cardiac myocytes and receptor‐mediated regulation of cardiac function; GRK3 has selectivity for the α1B‐ARs and for the thrombin receptor but exhibits less efficacy at β1‐ARs than GRK2.65 Their subcellular distribution in cardiac myocytes is also different. Consequently, GRK2 expression is increased in intercalated discs in rats with spontaneously hypertensive heart failure, whereas GRK3 expression is increased in cross‐striations in α‐actinin and Gα at Z‐lines.66Unlike the prohypertensive action of GRK2,33, 34 GRK3 may play a protective role in the regulation of blood pressure. Cardiac myocytes of spontaneously hypertensive heart failure rats have increased expression of GRK3 and GRK6 and altered distribution, including that of GRK2.66 GRK3 expression in human lymphocytes significantly and inversely correlates with systolic and diastolic ambulatory blood pressure.9 The protective role for GRK3 in the regulation of blood pressure is supported by findings in transgenic mice in which cardiac myocyte–restricted inhibition of endogenous GRK3 causes hypertension because of increased cardiac output caused in part by cardiac myocyte α1‐AR hyperresponsiveness.67 GRK3 is important in α1B‐AR signaling; GRK5 has a partial effect, whereas GRK2 has no effect.68 Although α‐ARs are key regulators of vascular resistance and GRK3 is expressed in the vasculature, it remains unknown whether or not GRK3 can regulate the blood pressure by exerting some functions in vascular resistance. In addition, GRK3 reportedly regulates the phosphorylation of D1R53 and D2R; however, its physiological consequence is not clear.G protein–coupled receptor kinase 4.The human GRK4 gene locus (4p16.3) is embedded in a gene cluster region on chromosome 4p16 that includes genes encoding dopamine receptor type 5 (4.p16.1) and α‐adducin (4p16.3), 2 variants of which (ADD1 and GRK4) are linked to hypertension.16, 69, 70 The human GRK4 gene is composed of 16 exons extending over 75 kb of DNA. Alternative splicing generates 4 isoforms of human GRK4 mRNA that differ in the presence or absence of exon 2 at the N‐terminal region and exon 15 in the C‐terminal region: GRK4α (578 amino acids, 66.5 kDa) is the full‐length isoform; GRK4β (546 amino acids, 62.9 kDa) lacks only the N‐terminal exon 2 (32‐codon deletion); GRK4γ (532 amino acids, 61.2 kDa) lacks only the C‐terminal exon 15 (46‐codon deletion); and the shortest splice variant is GRK4δ (500 amino acids, 57.6 kDa), missing both exons 2 and 15.71 In addition, 5 GRK4 splice variants (GRK4A–E) in rat and only 1 GRK4 splice in mouse have been reported. Only the GRKα isoform in humans, GRK4A in rats, and only GRK4 reported in mice are closely homologous (≈70%), whereas the mouse and rat GRK4 sequences retain 90% identity.Distribution of GRK4.As noted previously, GRK2, GRK3, GRK5, and GRK6 are ubiquitously expressed, whereas GRK4 is expressed in a limited number of tissues. GRK4, for example, is abundantly expressed in the testes and human myometrium and, to a lesser extent, in a few other tissues, including the artery, brain, kidney, and intestine, but has minimal expression in the normal heart.16, 71, 72 The distinct distribution of GRK4 indicates its vital role in the regulation of blood pressure. In both WKY rats and SHRs, GRK4 expression is strongly expressed in subapical membranes of renal proximal tubules (S1 and S3 segments), thick ascending limbs of the loop of Henle, and the distal convoluted tubules and much less in glomeruli.16, 72, 73 GRK4 is also present in rat renal resistance vessels, but its physiological function remains unclear. Basal GRK4 expression in the renal cortex is much higher in SHRs than in WKY rats, whereas cardiac GRK4 expression is similar in the 2 rat strains, indicating that the increased GRK4 expression in hypertension has organ specificity.72In our recent studies, we found that GRK4 is also expressed in the tunica media and adventitia of arteries from Sprague‐Dawley rats and C57BL/6J mice.21 GRK4 is expressed in both large and small vessels, including the thoracic aorta, superior mesenteric artery, carotid arteries, and renal artery, and there is no difference in GRK4 expression in these vessels. The physiological significance of GRK4 at the tunica adventitia, however, remains to be determined because GRK4 in this layer does not participate in the Ang II–mediated vasoconstriction.21 In addition, we found that GRK4 is expressed in the myocardium, which is involved in the regulation of myocardial ischemia. Overexpression of GRK4 or its variants in mice contributes to the aggravation of the ischemia induced by myocardial injury (L.P. Li, J. Yang, and C.Y. Zeng Ph.D., unpublished data, 2016).Regulation by GRK4 of blood pressure.The dopaminergic system and the renin–angiotensin system are important regulators of sodium balance and blood pressure, which are relevant to the pathogenesis and/or maintenance of hypertension.13, 15, 16, 17, 18, 54, 55, 56, 57, 59, 71, 72, 73, 74, 75, 76, 77, 78 The dopaminergic system exerts a paracrine regulatory role on renal sodium transport in the proximal tubule via its 5 receptor subtypes. Dopamine receptors, pharmacologically grouped into D1‐like (D1 and D5) and D2‐like (D2, D3, and D4) receptors, as with the Ang II receptors (AT1R and AT2R), are expressed in brush border and basolateral membranes of renal proximal tubules. AT1R mediates the vast majority of renal actions of Ang II, including renal tubule sodium reabsorption. In contrast to the stimulatory effect of Ang II on sodium transport in renal proximal tubules, the major consequence of the activation of dopamine receptors is the inhibition of sodium transport.13, 15, 16, 17, 18, 54, 55, 56, 57, 59, 71, 72, 73, 74, 75, 76, 77, 78 Increasingly, studies show that GRK4 plays an important physiological role in the long‐term control of blood pressure and in sodium homoeostasis via the regulation of the renal D1R, D3R, and AT1R.Studies have shown that increased GRK4 activity causes impaired renal D1R function in hypertension. GRK4 activity is increased in the kidneys of humans with essential hypertension, but the increased activity is caused not by increased renal GRK4 protein expression but rather by constitutively active variants of GRK4.16 In human renal proximal tubule cells, GRK4 constitutively phosphorylates the D1R" @default.
• W2473533692 created "2016-07-22" @default.
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• W2473533692 date "2016-07-06" @default.
• W2473533692 modified "2023-10-14" @default.
• W2473533692 title "G Protein–Coupled Receptor Kinases: Crucial Regulators of Blood Pressure" @default.
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