Published online before print March 17, 2008, doi: 10.1161/HYPERTENSIONAHA.107.096487
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(Hypertension. 2008;51:1449.)
© 2008 American Heart Association, Inc.
Brief Reviews |
G Protein–Coupled Receptor Kinase 4
Role in Blood Pressure Regulation
From the Department of Cardiology (C.Z.), Daping Hospital, Third Military Medical University, Chongqing, People’s Republic of China; Departments of Pediatrics (V.A.M.V., P.A.J.), Internal Medicine (G.M.E.), and Physiology and Biophysics (P.A.J.), Georgetown University Medical Center, Washington, DC; Division of Cardiovascular Medicine (S.M.W.), Vanderbilt University Medical Center, Nashville, Tenn; Department of Pathology (R.A.F.), Virginia University for the Health Sciences, Charlottesville, Va.
Correspondence to Chunyu Zeng, Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing City, People’s Republic of China. E-mail cyzeng1{at}hotmail.com
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Introduction |
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 Top Introduction GPCR Kinase FamilyGRK4 Localization and IsoformsGRK4 Splice VariantsPhysiological Role of GRK4GRK4 Polymorphisms and...References |
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Nearly 30% of middle-aged Americans have hypertension, but the prevalence is higher in non-Hispanic blacks and individuals >60 years of age (65%).1 There is a direct and quantitative relationship between higher blood pressure values and mortality. Although 30% to 50% is thought to be heritable, the genetic cause(s) of essential hypertension has been difficult to identify. More than 1 gene is undoubtedly involved, because Mendelian dominant and recessive traits are not readily discernible in hypertensive subjects, except in those with monogenic forms of hypertension. Moreover, in any hypertensive individual, risk-predisposing genes are engaged in a complex network of gene-gene and gene-environment interactions.2,3
The kidney plays a major role in the long-term regulation of blood pressure, and abnormal sodium chloride metabolism is frequently encountered in hypertension. Therefore, many studies have focused on the abnormal renal handling of sodium chloride in the pathogenesis of essential hypertension.2,4 Approximately 50% of subjects with essential hypertension are sodium chloride sensitive.5 Indeed, humans with salt-sensitive hypertension have increased sodium transport in the renal proximal tubule and medullary thick ascending limb, although distal tubular mechanisms may also be involved.6 The sodium retention in hypertension is because of enhanced sodium transport, per se, and/or a failure to respond appropriately to signals that decrease sodium transport. Sodium transport is regulated by natriuretic and antinatriuretic hormones and humoral agents, such as dopamine and angiotensin, which exert their effects via G protein–coupled receptors (GPCRs). Activation of certain postjunctional dopamine receptor subtypes (D1R, D3R, D4R, and D5R) and the angiotensin type 2 receptor inhibit, whereas activation of the postjunctional D2R and angiotensin type 1 receptor (AT1R) increase sodium transport.2,7
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GPCR Kinase Family |
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TopIntroductionGPCR Kinase FamilyGRK4 Localization and IsoformsGRK4 Splice VariantsPhysiological Role of GRK4GRK4 Polymorphisms and...References |
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The GPCR kinases (GRKs) are a 7-member family of serine/threonine protein kinases characterized by their ability to phosphorylate or modify and desensitize agonist-occupied cell surface membrane GPCRs. GRKs 1 and 7 belong to the rhodopsin family; GRKs 2 and 3 belong to the β-adrenergic receptor kinase family, and GRKs 4, 5, and 6 belong to the GRK4 family (Table 1). GRKs 1 and 7 are expressed exclusively in rods and cones, respectively, in the retina. GRKs 2, 3, 5, and 6 are ubiquitously expressed, whereas GRK4 expression is limited (see below).8 Overexpression of GRK2, GRK3, and especially GRK5 in human embryonic kidney cells desensitizes the D1R.9 GRK activity and GRK2 expression are increased in lymphocytes of patients with essential hypertension and spontaneously hypertensive rats (SHRs).10 Overexpression of GRK2 in vascular smooth muscles in mice produces hypertension and impairs the vasodilatory action of β-adrenergic receptors.11 The vasoconstrictor response to angiotensin II is also impaired in these mice, which is at odds with the increased reactivity and sensitivity to angiotensin II in essential hypertension.12 Interestingly, GRK2 activates the epithelial sodium channel by phosphorylating the C terminus of its β subunit, making it insensitive to the ubiquitin protein ligases Nedd4 and Nedd2.13 GRK5 overexpression in vascular smooth muscle cells in mice also increases blood pressure. The hypertension in male GRK5 transgenic mice is, in part, because of decreased β1-adrenergic receptor activity, whereas the high blood pressure in female mice is because of increased activity of AT1Rs.14 Dopamine D2R hypersensitivity occurs with disruption of the GRK6 gene in mice.15 Therefore, abnormalities of GRK6 gene can lead to D2R supersensitivity, which can result in a decrease in norepinephrine release, leading to decreased blood pressure or, alternatively, causing an increase in D2R-mediated sodium transport in renal proximal tubules, leading to an increased blood pressure, instead. Disruption of the D2R gene in mice, however, consistently leads to an increase in blood pressure, indicating a predominance of nonrenal mechanisms in the D2R-mediated regulation of blood pressure.2 GRK6 does not regulate the renal D1R,16 although it regulates intestinal D1Rs.17 The ubiquitous expression of GRKs 2, 3, 5, and 6 contrasts with the centrality of the kidney in the pathogenesis of rodent and human essential hypertension.2,8,18 It is also not clear whether the increases in vascular GRK activity and GRK2 and GRK5 expression follow or precede the hypertensive process in the SHR. It also remains to be determined whether gene variants of GRK2 and GRK5 are associated with human essential hypertension, although in a limited study we found no difference in the sequence of the coding region of GRK2 between hypertensive and normotensive human subjects.19 The limited expression of GRK42,8 and the fact that the GRK4 gene locus is linked to hypertension2 make the GRK4 gene an attractive candidate for a genetic determinant to human essential hypertension (Table 1).
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GRK4 Localization and Isoforms |
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TopIntroductionGPCR Kinase FamilyGRK4 Localization and IsoformsGRK4 Splice VariantsPhysiological Role of GRK4GRK4 Polymorphisms and...References |
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GRK4, as with the other members of the GRK4 family, is predominantly localized at the plasma membrane, as a result of palmitoylation of its C-terminal cysteine residues.8,20 GRK4 has a relatively low sequence homology across species, suggesting that it is subject to lower evolutionary pressure for sequence conservation and has evolved more rapidly than the other members of its subfamily and the β-adrenergic receptor kinase subfamily.20 It is interesting that GRK4 also differs from the other GRKs in tissue distribution. As noted previously GRKs 2, 3, 5, and 6 are ubiquitously expressed, whereas GRK4 is abundantly expressed in the testes and human myometrium and expressed at much lower levels in other tissues, including the brain8 and the kidney.19
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GRK4 Splice Variants |
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TopIntroductionGPCR Kinase FamilyGRK4 Localization and IsoformsGRK4 Splice VariantsPhysiological Role of GRK4GRK4 Polymorphisms and...References |
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GRK4 is the only GRK in which 4 splice variants (GRK4
, β, 
, and 
) have been identified in humans.8,19,20 GRK4, the full-length isoform, is most homologous with the other GRKs. GRK4β lacks exon 2, resulting in a 32-residue deletion that encompasses the phosphatidylinositol bisphosphate binding domain near the N terminus. GRK4 lacks exon 15, resulting in a 46-residue deletion near the C terminus, and GRK4, the shortest variant, lacks both exons 2 and 15. These human GRK4 splice variants are not found in other mammalian species. No alternative splicing has been reported in the mouse GRK4.20 Rat GRK4 undergoes alternative splicing, but in exons 6, 7, and 14, resulting in 5 Grk4 splice variants: Grk4A, B, C, D, and E. Rat Grk4A has 76% identity with GRK4, the longest of the human GRK4 splice variants. Rat Grk4B is characterized by a 31-amino acid deletion at the 5' end of the coding region, corresponding with exon 6 in the human GRK4 gene. Grk4C is characterized by a 157-amino acid deletion at the 5' end of the coding region, corresponding with exons 6 and 7 in the human GRK4 gene; Grk4C lacks the catalytic domain. GrkD lacks the 138-bp sequence of the 3' end-coding region, corresponding with exon 14 of the human GRK4 gene. Grk4A mRNA is abundant in spermatogenic cells and renal outer medulla. Grk4B mRNA is poorly expressed in testis and most rat tissues and is expressed mainly in the outer and inner medulla of the kidney. Grk4C is also strongly expressed in the outer medulla. A fifth Grk4 isoform, Grk4E, which lacks exons 6 and 14, may be the functional isoform expressed in rat kidney cortex.21 The differential tissue distribution of Grk4A, Grk4B, and Grk4E suggests that individual GRK4 splice variants may serve distinct physiological functions. |
Physiological Role of GRK4 |
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TopIntroductionGPCR Kinase FamilyGRK4 Localization and IsoformsGRK4 Splice VariantsPhysiological Role of GRK4GRK4 Polymorphisms and...References |
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Dopamine, produced by renal proximal tubules from circulating L-3,4-dihydroxyphenylalanine or filtered by the renal glomerulus, is responsible for >50% of sodium excretion during moderate sodium surfeit.2,7 Independent of innervation, renal proximal tubules synthesize dopamine that is not metabolized to norepinephrine.22 This is an important distinction between dopamine produced by neural tissue where dopamine is converted to norepinephrine and dopamine produced by nonneural tissue; otherwise an increase in dopamine production would also result in an increase in norepinephrine production, resulting in an increased ion transport because of the stimulation of
-adrenergic receptors. Such an action would then negate the decrease in ion transport caused by the stimulation of dopamine receptors.
Dopamine receptor function in renal proximal tubules is dysregulated in genetic hypertension. The importance of renal proximal tubule dopamine production in the pathogenesis of hypertension has recently been affirmed; selective disruption in the renal proximal tubule of aromatic amino acid decarboxylase, the enzyme that converts L-3,4-dihydroxyphenylalanine to dopamine, produces salt-sensitive hypertension in mice.23 Although renal dopamine production is not always decreased in genetic hypertension,2,7 the dopaminergic paracrine regulation of renal tubular sodium handling is consistently defective in human essential hypertension and rodent models of genetic hypertension.2,7 The renal dopaminergic defect in hypertension has been attributed to a diminished D1-like receptor inhibition of sodium and chloride transport: NHE3 (SLC9A3) and Cl/HCO3 (SLC26A6) at the luminal membrane and the electrogenic Na/HCO3 cotransporter, NBCe1A (SLC4A4), at the basolateral membrane of the renal proximal tubule and Na+-K+ ATPase at the basolateral membrane of the renal proximal tubule7 and thick ascending limb of Henle. The impairment of D1-like receptor stimulation of cAMP production in genetic hypertension is not caused by abnormalities in the primary structure of the D1-like receptors (D1R and D5R), adenylyl cyclases, and protein kinases A and C.2,7,24,25 The GS and adenylyl cyclase enzyme are not defective, per se, because the ability of the parathyroid hormone, guanosine-5'-O-C3-thiotriphosphate (GTPS), or forskolin to stimulate adenylyl cyclase is not impaired in renal proximal tubules of spontaneously hypertensive rats (SHRs)26 or in renal proximal tubule cells from hypertensive patients with impaired D1R function.19 Renal proximal tubule NHE3, Cl/HCO3 exchanger, NaHCO3 exchanger, and Na+-K+ ATPase activities can be directly inhibited in SHRs, indicating that there is no primary defect in these ion transporters or Na+-K+ ATPase, per se.25 Indeed, the natriuretic effect of parathyroid hormone is not impaired in humans with essential hypertension or in SHRs.27 The phosphaturic response to parathyroid hormone may not also be impaired in SHRs.28
Regardless of the extent of renal D1-like receptor protein expression, the D1-like receptor is always uncoupled from its GS (not to Gi3 or Gβ25)/effector protein complex in the kidney of SHRs and renal proximal tubule cells from subjects with essential hypertension. The uncoupling of the renal D1-like receptor in rodent genetic hypertension is receptor and organ specific and cosegregates with and precedes the onset of hypertension.2,24 Because the major receptor involved in the dopamine-mediated natriuresis is probably the D1R, we have suggested that the defective renal D1-like receptor in genetic hypertension probably involves the D1R rather than the D5R. There is evidence for a constitutive desensitization of the renal D1R but not the D5R in hypertension.29 The renal D5R action is not impaired in the SHRs; rather, renal D5R expression is decreased.30
The uncoupling of the D1R (in the absence of ligand occupation) from its effector proteins in the kidney in essential hypertension is associated with increased serine-phosphorylation of the D1R, which is internalized and poorly recycled back to the plasma membrane.31 This is caused by a constitutively increased GRK4 activity19 (Figure 1). An impaired protein phosphatase 2A function (Figures 1 and 2
) may also play a role in the hyperphosphorylation of the renal D1R in SHRs32; however, the activity of this enzyme in renal proximal tubule cells from hypertensive subjects remains to be determined. In human renal proximal tubule cells, antisense oligonucleotides to GRK4 ameliorate the desensitization of the D1R to a greater extent than that produced by antisense oligonucleotides to GRK2, indicating that GRK4 is more important than GRK2 in the desensitization of the human D1Rs.33 Renal GRK4 plays a role in the high blood pressure of SHRs.21 Both GRK4 and GRK2 have been implicated in the D1R dysfunction in obese rats.34 GRK2 activity is increased in SHRs and is responsible for the impaired renal D1R function with aging and hyperglycemia.35
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GRK4 activity is increased in 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 GRK4.19 However, SHRs, which do not have activating variants of Grk4 (unpublished data), have increased renal cortical membrane Grk4 expression and serine-phosphorylated D1Rs relative to Wistar-Kyoto rats. Selective renal cortical inhibition of Grk4 expression decreases D1R phosphorylation, increases sodium excretion, and attenuates the increase in arterial blood pressure with age in SHRs, effects that are not observed in Wistar-Kyoto rats. These studies provide direct evidence of a crucial role of increased renal GRK4 expression in the D1R-mediated regulation of sodium excretion and blood pressure in the SHR.21
Increased activity of GRK4 because of constitutively active GRK4 variants causes the decrease in D1R function in renal proximal tubule cells from hypertensive humans. In these cells, knockdown of GRK4 gene expression decreases D1R phosphorylation and ameliorates the ability to produce cAMP in response to agonist stimulation,19 but the GRK4 splice variant regulating the D1R has not been determined. All of the GRK4 splice variants are expressed in human renal proximal tubule cells. GRK4 gene variants (R65L, A142V, and A486V), heterologously expressed in Chinese hamster ovary cells, increase the serine phosphorylation and impair the function of D1Rs. In contrast, the constitutive phosphorylation of D1R in HEK293 cells is mediated exclusively by the GRK4; the β, , and variants are ineffective. The cause of the differences in GRK4 splice variant effect on D1R between HEK293 and Chinese hamster ovary cells is not clear. It is possible that the lack of effect of human GRK4 in HEK293 cells is because of differences in the cellular environment, indicating cell-specific function. Whether overexpression of human GRK4 gene variants in mice also impairs D1R function and increases blood pressure remains to be determined. We do know that human GRK4 gene variants are important in the regulation of D1Rs in vivo. Mice overexpressing the human GRK4 wild-type gene are normotensive and salt resistant19 depending on the genetic background,36 whereas mice overexpressing the human GRK4 142V are hypertensive even on a normal NaCl intake.19,37 In contrast, human GRK4 486V transgenic mice, depending on the genetic background, become hypertensive only after an increase in sodium intake.36 The increase in blood pressure in human GRK4 142V transgenic mice is not related to chromosomal integration, copy number, or renal human GRK4 mRNA level.37 Thus, it is the presence of the heterologously expressed human GRK4 variant rather than the amount of human GRK4 that impairs D1R function and produces hypertension in transgenic mice and probably in human essential hypertension.
The D1R also plays a role in sodium balance by inhibition of Na+-K+-ATPase activity in jejunal cells38; dopamine fails to inhibit Na+-K+-ATPase activity in jejunal epithelial cells from SHRs.38 In intestinal cells, however, GRK6, rather than GRK4, regulates D1R function,39 which is different from that observed in the kidney.16,21
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GRK4 Polymorphisms and Hypertension |
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TopIntroductionGPCR Kinase FamilyGRK4 Localization and IsoformsGRK4 Splice VariantsPhysiological Role of GRK4GRK4 Polymorphisms and...References |
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The frequency of GRK4 polymorphisms (R65L, A142V, A486V, V247I, A253T, and G562D) varies according to ethnicity. There is limited haplotype diversity, with differing haplotype frequencies among the ethnic groups.40 GRK4 65L and 142V are more frequent among Ghanaians and blacks than the other ethnic groups studied (Chinese, Hispanic, Japanese, and whites),40 whereas GRK4 486V is more frequent among Chinese and Japanese subjects40,41 (Table 2).
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There is increasing evidence that GRK4 plays an important role in hypertension, especially in salt-sensitive hypertension. The GRK4 locus (4p16.3) is linked to hypertension.2 In Ghanaians, multilocus genotype combinations of angiotensin-converting enzyme (ACE) I/D and GRK4 R65L variants, but not single locus effects at these genes, are the most predictive of both systolic and diastolic hypertension, regardless of salt-sensitivity status.42 The 3 major substitutions in GRK4 (R65L, A142V, and A486V) have now been examined in 3 other, independent studies for essential hypertension. In 1 study, GRK4 486V is associated with hypertension (and systolic blood pressure elevation) in Australian white subjects.43 In another study, GRK4 486V is associated with hypertension in Italian subjects,44 reminiscent of the phenotype of the human GRK4 486V transgenic mice.36 In a study of northern Han Chinese subjects, the GRK4 65L, 142V, and A486 haplotypes are associated with a 6-fold higher risk of systolic and diastolic hypertension45 (Table 2). In another report of the same Han Chinese data from the same group, the A486V polymorphism is also shown to be associated with hypertension, but the allele that increased the risk is 486V.46 To estimate the effects of the R65L, A142V, and A486V variants on hypertension, we performed a meta-analysis, using the data culled from the studies described above, except for the results for A486V in the Han Chinese subjects, because the data from the 2 articles are identical but the conclusions are opposite, preventing us from resolving the direction of association (Figure 3). The meta-analysis clearly shows a significant association of 486V with hypertension with an odds ratio of 1.5 (95% CI: 1.2 to 1.9). Neither of the other meta-analyses for the other variants indicates a significant association, but it should be noted that even our own previous results with a Ghanaian population suggest that single locus effects may not be detectable in such a complex phenotype. Therefore, it is important to perform a multilocus analysis to test for gene-gene interactions in hypertension.
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2 analysis, with P<0.1 considered as significant. We also report the I2 value, which estimates the proportion of total variation that is because of heterogeneity.The ability to excrete a sodium load in Japanese subjects with essential hypertension is inversely related to the number of GRK4 single nucleotide polymorphisms in the 2 alleles of the GRK4 gene. However, the presence of 3 GRK4 variants impairs the natriuretic effect of a dopaminergic drug, even in normotensive subjects. Thus, salt sensitivity may be imparted by GRK4 gene variants. Consistent with this model, in a study comparing genetic predisposition of salt-sensitive to salt-resistant hypertension in a Japanese cohort, each of the 3 variants has a significant association with salt sensitivity, and using all 3 together predicts salt sensitivity correctly in 94% of our samples. In the same Japanese study, the single best genetic model for low-renin hypertension includes only GRK4 A142V, by itself, or GRK4 A142V and CYP11B2, with an estimated predictive accuracy of 78%.41 These results show that the underlying genetic models of salt-sensitive, low-renin, and possibly other subclasses of hypertension are different (Table 2).
Zhu et al47 determined the association of GRK4 variants (65L, 142V, and 486V) with blood pressure in black and white American twin subjects. Single-locus analyses revealed a significant interaction and a dose effect between 65L and age for systolic blood pressure. Individuals who are homozygous for the 65L-142V-A486 haplotype have a 1.05-mm Hg steeper increase in systolic blood pressure per year of increase in age compared with those homozygous for the most common R65-A142-A486 haplotype.47 In black adolescents with GRK4 65L, mental stress causes an increase in blood pressure and a decrease in sodium excretion. One study, however, did not find an association of GRK4 486V with the top fifth percentile of diastolic blood pressure of subjects with white European ancestry.48 This study is not included in the meta-analysis, because the phenotypes used are not directly comparable to the other studies.
In summary, a constitutively active GRK4 splice variant may be important in the pathogenesis of hypertension. The limited number of GPCRs regulated by GRK4 (Table 3) and its limited tissue/organ expression make GRK4 an attractive candidate gene for essential hypertension in humans.2
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Perspectives
Dysfunction of renal dopamine and AT1Rs is involved into the pathogenesis of hypertension. GRK4 could be the common factor, which regulates GPCRs expressed in the kidney. As aforementioned, GRK4 activity is increased in hypertensive states, which impairs renal D1R function,2,19 and our preliminary studies show that GRK4 also increases AT1R expression and function.49 Moreover, suppression of renal GRK4 expression restores renal D1R function and lowers blood pressure in SHRs.21 GRK4 could be an attractive antihypertensive target.
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Acknowledgments |
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Sources of Funding
These studies were supported in part by grants from the National Institutes of Health (HL 23081, DK 39308, HL68686, DK52612, and HL41618), the National Natural Science Foundation of China (30470728 and 30672199), and the National Basic Research Program of China (973 Program, 2008CB17308).
Disclosures
R.A.F. and P.A.J. were awarded a US Patent (No. 6,660,474) on "GRK mutants in essential hypertension" and formed the company Hypogen, Inc.
Received June 16, 2007; first decision July 12, 2007; accepted February 15, 2008.
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