G protein coupled receptor kinase 4


Gene Symbol: G protein coupled receptor kinase 4
Description: G protein-coupled receptor kinase 4
Alias: GPRK2L, GPRK4, GRK4a, IT11, G protein-coupled receptor kinase 4, G protein-coupled receptor kinase 2-like
Species: human

Top Publications

  1. Bengra C, Mifflin T, Khripin Y, Manunta P, Williams S, Jose P, et al. Genotyping of essential hypertension single-nucleotide polymorphisms by a homogeneous PCR method with universal energy transfer primers. Clin Chem. 2002;48:2131-40 pubmed
    ..We also observed a significant association (P = 0.034) between one SNP (A486V) and an Italian population of mildly hypertensive patients. ..
  2. Speirs H, Katyk K, Kumar N, Benjafield A, Wang W, Morris B. Association of G-protein-coupled receptor kinase 4 haplotypes, but not HSD3B1 or PTP1B polymorphisms, with essential hypertension. J Hypertens. 2004;22:931-6 pubmed
    ..Neither of the HSD3B1 or PTP1B variants were associated with HT. Genetic variation in GRK4gamma was associated with HT in the subjects studied. ..
  3. Gu D, Su S, Ge D, Chen S, Huang J, Li B, et al. Association study with 33 single-nucleotide polymorphisms in 11 candidate genes for hypertension in Chinese. Hypertension. 2006;47:1147-54 pubmed
    ..These findings support the multigenic nature of the etiology of essential hypertension and propose a potential gene-gene interactive model for future studies. ..
  4. Wang Y, Li B, Zhao W, Liu P, Zhao Q, Chen S, et al. Association study of G protein-coupled receptor kinase 4 gene variants with essential hypertension in northern Han Chinese. Ann Hum Genet. 2006;70:778-83 pubmed
    ..001). A total of 6 haplotypes were observed in the entire population, with the haplotypes L-V-A and R-A-A being found to be significantly related to hypertension (P= 0.001). ..
  5. Amosco M, Tavera G, Villar V, Naniong J, David Bustamante L, Williams S, et al. Non-additive effects of ACVR2A in preeclampsia in a Philippine population. BMC Pregnancy Childbirth. 2019;19:11 pubmed publisher
  6. Zilbermint M, Hannah Shmouni F, Stratakis C. Genetics of Hypertension in African Americans and Others of African Descent. Int J Mol Sci. 2019;20: pubmed publisher
    ..Understanding the different genetics of hypertension among various groups is essential for effective precision-guided medical therapy of high blood pressure. ..
  7. Lansford J, Dharmasiri U, Chai S, Hunsucker S, Bortone D, Keating J, et al. Computational modeling and confirmation of leukemia-associated minor histocompatibility antigens. Blood Adv. 2018;2:2052-2062 pubmed publisher
    ..Computational analysis of genomic and transcriptomic data can reliably predict leukemia-associated mHA and can be used to guide targeted mHA discovery. ..
  8. Kuwasako K, Hay D, Nagata S, Murakami M, Kitamura K, Kato J. Functions of third extracellular loop and helix 8 of Family B GPCRs complexed with RAMPs and characteristics of their receptor trafficking. Curr Protein Pept Sci. 2013;14:416-28 pubmed
    ..In this review, we describe these studies and consider their implications for other Family B GPCRs that can interact with RAMPs. ..
  9. Thompson M, Cole D, Jose P, Chidiac P. G protein-coupled receptor accessory proteins and signaling: pharmacogenomic insights. Methods Mol Biol. 2014;1175:121-52 pubmed publisher
    ..An understanding of the pharmacogenomics of GPCR and accessory protein signaling provides the basis for examining both GPCR pharmacogenetics and the genetics of monogenic disorders that result from disruption of given receptor systems. ..

More Information


  1. Wang X, Luo H, Chen C, Chen K, Wang J, Cai Y, et al. Prenatal lipopolysaccharide exposure results in dysfunction of the renal dopamine D1 receptor in offspring. Free Radic Biol Med. 2014;76:242-50 pubmed publisher
    ..Normalization of renal D1R function by amelioration of oxidative stress may be a therapeutic target of fetal programming of hypertension. ..
  2. Li L, Homan K, Vishnivetskiy S, Manglik A, Tesmer J, Gurevich V, et al. G Protein-coupled Receptor Kinases of the GRK4 Protein Subfamily Phosphorylate Inactive G Protein-coupled Receptors (GPCRs). J Biol Chem. 2015;290:10775-90 pubmed publisher
  3. Zhao Y, Vanhoutte P, Leung S. α1 -Adrenoceptor activation of PKC-ε causes heterologous desensitization of thromboxane receptors in the aorta of spontaneously hypertensive rats. Br J Pharmacol. 2015;172:3687-701 pubmed publisher
    ..This heterologous desensitization is a consequence of the chronic exposure to high arterial pressure. ..
  4. Rayner B, Ramesar R. The importance of G protein-coupled receptor kinase 4 (GRK4) in pathogenesis of salt sensitivity, salt sensitive hypertension and response to antihypertensive treatment. Int J Mol Sci. 2015;16:5741-9 pubmed publisher
    ..It may also underlie the difference in hypertension between different geographically derived population groups, and form a basis for pharmacogenomic approaches to treatment of hypertension. ..
  5. Lu X, Ye Z, Zheng S, Ren H, Zeng J, Wang X, et al. Long-Term Exposure of Fine Particulate Matter Causes Hypertension by Impaired Renal D1 Receptor-Mediated Sodium Excretion via Upregulation of G-Protein-Coupled Receptor Kinase Type 4 Expression in Sprague-Dawley Rats. J Am Heart Assoc. 2018;7: pubmed publisher
    ..5-induced hypertension. ..
  6. Mushegian A, Gurevich V, Gurevich E. The origin and evolution of G protein-coupled receptor kinases. PLoS ONE. 2012;7:e33806 pubmed publisher
    ..Thus, GRKs apparently emerged before animals and rapidly expanded in true Metazoa, most likely due to the need for rapid signalling adjustments in fast-moving animals. ..
  7. Huang H, Li X, Zheng S, Chen Y, Chen C, Wang J, et al. Downregulation of Renal G Protein-Coupled Receptor Kinase Type 4 Expression via Ultrasound-Targeted Microbubble Destruction Lowers Blood Pressure in Spontaneously Hypertensive Rats. J Am Heart Assoc. 2016;5: pubmed
  8. Jones E, Spence J, McIntyre A, Nondi J, Gogo K, Akintunde A, et al. High Frequency of Variants of Candidate Genes in Black Africans with Low Renin-Resistant Hypertension. Am J Hypertens. 2017;30:478-483 pubmed publisher
    ..These preliminary findings suggest that this novel approach may assist in understanding the genetic architecture of RHT in Blacks and explain their two fold risk of stroke. ..
  9. Blaukat A, Pizard A, Breit A, Wernstedt C, Alhenc Gelas F, Muller Esterl W, et al. Determination of bradykinin B2 receptor in vivo phosphorylation sites and their role in receptor function. J Biol Chem. 2001;276:40431-40 pubmed
    ..The differential usage of clustered phosphoacceptor sites points to distinct roles of multiple kinases in controlling G protein-coupled receptor function. ..
  10. Maurin T, Melko M, Abekhoukh S, Khalfallah O, Davidovic L, Jarjat M, et al. The FMRP/GRK4 mRNA interaction uncovers a new mode of binding of the Fragile X mental retardation protein in cerebellum. Nucleic Acids Res. 2015;43:8540-50 pubmed publisher
    ..Considering the role of GRK4 in GABAB receptors desensitization, our results suggest that an increased GRK4 levels in FXS might contribute to cerebellum-dependent phenotypes through a deregulated desensitization of GABAB receptors. ..
  11. Zhu H, Lu Y, Wang X, Snieder H, Treiber F, Harshfield G, et al. The G protein-coupled receptor kinase 4 gene modulates stress-induced sodium excretion in black normotensive adolescents. Pediatr Res. 2006;60:440-2 pubmed
    ..The 65L allele of the GRK4 gene is associated with stress-induced U(Na)V reduction, suggesting impaired sodium handling in affected black youth. ..
  12. Friedman E, Moran D, Ben Avraham D, Yanovich R, Atzmon G. Novel candidate genes putatively involved in stress fracture predisposition detected by whole-exome sequencing. Genet Res (Camb). 2014;96:e004 pubmed publisher
    ..Exome sequencing seemingly unravelled novel candidate genes as involved in SF pathogenesis and predisposition. ..
  13. Ambrose C, James M, Barnes G, Lin C, Bates G, Altherr M, et al. A novel G protein-coupled receptor kinase gene cloned from 4p16.3. Hum Mol Genet. 1992;1:697-703 pubmed
    ..Such kinases are thought to participate in desensitization of specific receptors, thereby blocking further signal transduction. This gene must now be carefully scrutinized to determine whether it might be involved in HD. ..
  14. Perroy J, Adam L, Qanbar R, Chénier S, Bouvier M. Phosphorylation-independent desensitization of GABA(B) receptor by GRK4. EMBO J. 2003;22:3816-24 pubmed
  15. Yang J, Villar V, Jones J, Jose P, Zeng C. G protein-coupled receptor kinase 4: role in hypertension. Hypertension. 2015;65:1148-55 pubmed publisher
  16. Allen S, Parthasarathy G, Darke P, Diehl R, Ford R, Hall D, et al. Structure and Function of the Hypertension Variant A486V of G Protein-coupled Receptor Kinase 4. J Biol Chem. 2015;290:20360-73 pubmed publisher
    ..Phosphopeptide mapping by mass spectrometry indicates an increased rate of autophosphorylation of a number of residues in GRK4α A486V relative to wild-type GRK4α, including Ser-485 in the kinase C-tail. ..
  17. Kuwasako K, Kitamura K, Nagata S, Hikosaka T, Kato J. Function of the cytoplasmic tail of human calcitonin receptor-like receptor in complex with receptor activity-modifying protein 2. Biochem Biophys Res Commun. 2010;392:380-5 pubmed publisher
    ..Thus, the hCRLR C-tail is crucial for AM-evoked cAMP production and internalization of the CRLR/RAMP2, while the receptor internalization is dependent on the aforementioned GPCR kinases, but not Gs coupling. ..
  18. Kuwasako K, Sekiguchi T, Nagata S, Jiang D, Hayashi H, Murakami M, et al. Inhibitory effects of two G protein-coupled receptor kinases on the cell surface expression and signaling of the human adrenomedullin receptor. Biochem Biophys Res Commun. 2016;470:894-9 pubmed publisher
    ..Thus, we provided new insight into the function of GRKs in agonist-unstimulated GPCR trafficking using a recombinant AM1 receptor and further determined the region of the CLR C-tail responsible for this GRK function. ..
  19. Diao Z, Asico L, Villar V, Zheng X, Cuevas S, Armando I, et al. Increased renal oxidative stress in salt-sensitive human GRK4γ486V transgenic mice. Free Radic Biol Med. 2017;106:80-90 pubmed publisher
    ..Chronic tempol treatment partially prevented the salt-sensitivity of hGRK4γ486V mice. Thus, hGRK4γ486V causes salt-sensitive hypertension due, in part, to defective renal antioxidant mechanisms. ..
  20. Doris P. Promoting regulatory gene variation in sodium reabsorption. Hypertension. 2008;52:623-4 pubmed publisher
  21. Sallese M, Lombardi M, De Blasi A. Two isoforms of G protein-coupled receptor kinase 4 identified by molecular cloning. Biochem Biophys Res Commun. 1994;199:848-54 pubmed
    ..This demonstrates the existence of two isoforms of GRK4 which were named GRK4A and GRK4B in the presence or absence of the insert, respectively...
  22. Keever L, Jones J, Andresen B. G protein-coupled receptor kinase 4gamma interacts with inactive Galpha(s) and Galpha13. Biochem Biophys Res Commun. 2008;367:649-55 pubmed publisher
    ..This evidence suggests that binding to inactive Galpha(s) and Gbeta may explain the constitutive activity of GRK4gamma towards Galpha(s)-coupled receptors. ..
  23. Lee M, Kwon D, Park J. The impacts of the interaction of genetic variation, CYP11?2 and NEDD4L, with sodium intake on pediatric obesity with gender difference: a 3-year panel study. Int J Obes (Lond). 2017;41:542-550 pubmed publisher
    ..Girls with hetero/mutant allele of this gene should reduce their daily Na intake to prevent obesity. ..
  24. Zhu H, Lu Y, Wang X, Treiber F, Harshfield G, Snieder H, et al. The G protein-coupled receptor kinase 4 gene affects blood pressure in young normotensive twins. Am J Hypertens. 2006;19:61-6 pubmed
    ..Our data indicate that the R65L polymorphism of the GRK4 gene plays a role in BP regulation in adolescents and young adults. ..
  25. Premont R, Macrae A, Stoffel R, Chung N, Pitcher J, Ambrose C, et al. Characterization of the G protein-coupled receptor kinase GRK4. Identification of four splice variants. J Biol Chem. 1996;271:6403-10 pubmed
  26. Chen K, Fu C, Chen C, Liu L, Ren H, Han Y, et al. Role of GRK4 in the regulation of arterial AT1 receptor in hypertension. Hypertension. 2014;63:289-96 pubmed publisher
    ..This study provides a mechanism by which GRK4, via regulation of arterial AT(1)R expression and function, participates in the pathogenesis of conduit vessel abnormalities in hypertension. ..
  27. Wang Z, Armando I, Asico L, Escano C, Wang X, Lu Q, et al. The elevated blood pressure of human GRK4gamma A142V transgenic mice is not associated with increased ROS production. Am J Physiol Heart Circ Physiol. 2007;292:H2083-92 pubmed
    ..We conclude that the elevated blood pressure of hGRK4gamma A142V transgenic mice is due mainly to the effect of hGRK4gamma A142V transgene acting via D(1)R and increased ROS production is not a contributor. ..
  28. Hasenkamp S, Telgmann R, Staessen J, Hagedorn C, Dördelmann C, Bek M, et al. Characterization and functional analyses of the human G protein-coupled receptor kinase 4 gene promoter. Hypertension. 2008;52:737-46 pubmed publisher
    ..The 4 identified genetic variants within this region exert allele-specific impact on both cell type- and stimulation-dependent transcription and may affect the expression balance of renal G protein-coupled receptor kinase 4. ..
  29. Bhatnagar V, O Connor D, Brophy V, Schork N, Richard E, Salem R, et al. G-protein-coupled receptor kinase 4 polymorphisms and blood pressure response to metoprolol among African Americans: sex-specificity and interactions. Am J Hypertens. 2009;22:332-8 pubmed publisher
    ..Men with a GRK4 A142 were less responsive to metoprolol if they had a GRK4 L65 variant. The effect of GRK4 variants and blood pressure response to metoprolol should be studied in larger clinical trials. ..
  30. Chougule R, P S, Salimath B, Sosalegowda A. Buffalo colostrum ?-lactoglobulin inhibits VEGF-induced angiogenesis by interacting with G protein-coupled receptor kinase. Appl Biochem Biotechnol. 2013;171:366-81 pubmed publisher
  31. Jose P, Soares da Silva P, Eisner G, Felder R. Dopamine and G protein-coupled receptor kinase 4 in the kidney: role in blood pressure regulation. Biochim Biophys Acta. 2010;1802:1259-67 pubmed publisher
    ..Knowledge of the numerous blood pressure regulatory pathways involving angiotensin and dopamine may provide new therapeutic approaches to the pharmacological regulation of sodium excretion and ultimately blood pressure control. ..
  32. Van Hee V, Adar S, Szpiro A, Barr R, Diez Roux A, Bluemke D, et al. Common genetic variation, residential proximity to traffic exposure, and left ventricular mass: the multi-ethnic study of atherosclerosis. Environ Health Perspect. 2010;118:962-9 pubmed publisher
    ..Further understanding of how genes modify effects of air pollution on CVD may help guide research efforts into specific mechanistic pathways. ..
  33. Hager A, Bildau J, Kreuder J, Kaemmerer H, Hess J. Impact of genomic polymorphism on arterial hypertension after aortic coarctation repair. Int J Cardiol. 2011;151:63-8 pubmed publisher
    ..The correlation of the ACE I/D and the ADRB1 c.1165C>G polymorphism to nocturnal dipping and blood pressure at nighttime needs further confirmation. ..
  34. Wang Z, Zeng C, Villar V, Chen S, Konkalmatt P, Wang X, et al. Human GRK4γ142V Variant Promotes Angiotensin II Type I Receptor-Mediated Hypertension via Renal Histone Deacetylase Type 1 Inhibition. Hypertension. 2016;67:325-34 pubmed publisher
  35. Xiao P, Huang X, Huang L, Yang J, Li A, Shen K, et al. G protein-coupled receptor kinase 4-induced cellular senescence and its senescence-associated gene expression profiling. Exp Cell Res. 2017;360:273-280 pubmed publisher
    ..These results unveil a novel function of GRK4 on triggering a p53-independent cellular senescence, which involves an intricate signaling network. ..
  36. Jose P, Felder R, Yang Z, Zeng C, Eisner G. Gastrorenal Axis. Hypertension. 2016;67:1056-63 pubmed publisher
  37. Irvin M, Lynch A, Kabagambe E, Tiwari H, Barzilay J, Eckfeldt J, et al. Pharmacogenetic association of hypertension candidate genes with fasting glucose in the GenHAT Study. J Hypertens. 2010;28:2076-83 pubmed publisher
    ..001). Further examination of these genes and their relationships with cardiometabolic disease could foster development of pharmacogenetic guidelines aimed to prevent increases in fasting glucose during antihypertensive treatment. ..
  38. Sun C, Zhang W. G protein-coupled receptor kinase 4 gene variants are not associated with preeclampsia in Northern Han Chinese. Hypertens Res. 2010;33:683-7 pubmed publisher
    ..The GRK4 (T-rs1024323-C and T-rs1801058-C) polymorphisms were not associated with a risk of PE in the present Northern Han Chinese study group. Thus, the GRK4 polymorphisms do not seem to have an important role in PE in this population. ..
  39. Rankin M, Marinec P, Cabrera D, Wang Z, Jose P, Sibley D. The D1 dopamine receptor is constitutively phosphorylated by G protein-coupled receptor kinase 4. Mol Pharmacol. 2006;69:759-69 pubmed
    ..Furthermore, our data provide direct evidence that, in contrast to current dogma, GRKs can (at least in some instances) constitutively phosphorylate GPCRs in the absence of agonist activation resulting in constitutive desensitization. ..
  40. Staessen J, Kuznetsova T, Zhang H, Maillard M, Bochud M, Hasenkamp S, et al. Blood pressure and renal sodium handling in relation to genetic variation in the DRD1 promoter and GRK4. Hypertension. 2008;51:1643-50 pubmed publisher
    ..In conclusion, renal sodium handling and BP were associated with genetic variation in the DRD1 promoter. The between-family variance component excluded population stratification for BP, but not for the renal phenotypes. ..
  41. Sallese M, Mariggio S, Collodel G, Moretti E, Piomboni P, Baccetti B, et al. G protein-coupled receptor kinase GRK4. Molecular analysis of the four isoforms and ultrastructural localization in spermatozoa and germinal cells. J Biol Chem. 1997;272:10188-95 pubmed
  42. Sanada H, Yoneda M, Yatabe J, Williams S, Bartlett J, White M, et al. Common variants of the G protein-coupled receptor type 4 are associated with human essential hypertension and predict the blood pressure response to angiotensin receptor blockade. Pharmacogenomics J. 2016;16:3-9 pubmed publisher
    ..These studies showed for the first time the association between GRK4(142V) and a larger decrease in BP with ARBs in hypertensive patients. ..
  43. Lazari M, Liu X, Nakamura K, Benovic J, Ascoli M. Role of G protein-coupled receptor kinases on the agonist-induced phosphorylation and internalization of the follitropin receptor. Mol Endocrinol. 1999;13:866-78 pubmed
    ..The finding that inhibitors of GRK2 and GRK6 impair phosphorylation, but only the inhibitors of GRK2 impair internalization, suggests that different GRKs have differential effects on receptor internalization. ..
  44. Yu C, Yin L, Tu Z, Liu D, Luo W. The regulatory role of dopamine receptor D1 on PP2A via SUMO-1 modification. Eur Rev Med Pharmacol Sci. 2017;21:3270-3276 pubmed
  45. Villar V, Jones J, Armando I, Palmes Saloma C, Yu P, Pascua A, et al. G protein-coupled receptor kinase 4 (GRK4) regulates the phosphorylation and function of the dopamine D3 receptor. J Biol Chem. 2009;284:21425-34 pubmed publisher
    ..These data demonstrate that GRK4, specifically the GRK4-gamma and GRK4-alpha isoforms, phosphorylates the D(3) receptor and is crucial for its signaling in human proximal tubule cells. ..
  46. Villar V, Armando I, Sanada H, Frazer L, Russo C, Notario P, et al. Novel role of sorting nexin 5 in renal D(1) dopamine receptor trafficking and function: implications for hypertension. FASEB J. 2013;27:1808-19 pubmed publisher
    ..These studies demonstrate an essential role for SNX5 in regulating D1R function, which may have important diagnostic, prognostic, and therapeutic implications in the management of essential hypertension. ..
  47. Menard L, Ferguson S, Barak L, Bertrand L, Premont R, Colapietro A, et al. Members of the G protein-coupled receptor kinase family that phosphorylate the beta2-adrenergic receptor facilitate sequestration. Biochemistry. 1996;35:4155-60 pubmed
    ..Our results demonstrate that phosphorylation per se, but not the interaction with a specific GRK, is required to facilitate beta2AR sequestration. ..
  48. Liu C, Xi B. Pooled analyses of the associations of polymorphisms in the GRK4 and EMILIN1 genes with hypertension risk. Int J Med Sci. 2012;9:274-9 pubmed publisher
    ..In addition, there were significant associations of rs2011616 and rs2304682 polymorphisms in the EMILIN1 gene with hypertension among Japanese. ..
  49. Kurnik D, Cunningham A, Sofowora G, Kohli U, Li C, Friedman E, et al. GRK5 Gln41Leu polymorphism is not associated with sensitivity to beta(1)-adrenergic blockade in humans. Pharmacogenomics. 2009;10:1581-7 pubmed publisher
    ..We hypothesized that the GRK5 Gln41Leu variant contributes to interindividual variability in response to beta-blockade and to the ethnic difference in sensitivity between black and Caucasian individuals...
  50. Zhang H, Sun Z, Liu S, Yang L. Association between GRK4 and DRD1 gene polymorphisms and hypertension: a meta-analysis. Clin Interv Aging. 2016;11:17-27 pubmed publisher
    ..Rs4532 locus was associated with hypertension in East Asians (OR =1.833, 95% CI =1.415-2.376, P,0.001) but not in Caucasians. These data provide possible references for future case-control studies in hypertension. ..
  51. Lee M, Kim M, Kim S, Park H, Park C, Park H. Gender-based differences on the association between salt-sensitive genes and obesity in Korean children aged between 8 and 9 years. PLoS ONE. 2015;10:e0120111 pubmed publisher
    ..Obese children with the specific gene variants are recommended to reduce their sodium intake. ..
  52. Watanabe H, Xu J, Bengra C, Jose P, Felder R. Desensitization of human renal D1 dopamine receptors by G protein-coupled receptor kinase 4. Kidney Int. 2002;62:790-8 pubmed
    ..However, the early phase of homologous desensitization is regulated by a non-GRK-mediated pathway. ..
  53. Rayner B, Ramesar R, Steyn K, Levitt N, Lombard C, Charlton K. G-protein-coupled receptor kinase 4 polymorphisms predict blood pressure response to dietary modification in Black patients with mild-to-moderate hypertension. J Hum Hypertens. 2012;26:334-9 pubmed publisher
    ..These data may provide at least one among a range of clinical tools to target selected hypertensives to dietary intervention. ..