GRK4 Gene

Name	G protein-coupled receptor kinase 4
Description	This gene encodes a member of the guanine nucleotide-binding protein (G protein)-coupled receptor kinase subfamily of the Ser/Thr protein kinase family. The protein phosphorylates the activated forms of G protein-coupled receptors thus initiating its deactivation. This gene has been linked to both genetic and acquired hypertension. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n G protein‐coupled receptor kinase 4 (GRK4) is emerging as a key regulator of renal and vascular receptor signaling that profoundly influences sodium balance and blood pressure homeostasis. GRK4 phosphorylates dopamine receptors—most notably the D1 and D3 subtypes—in renal proximal tubule cells, thereby promoting their desensitization and internalization and impairing dopaminergic‐mediated natriuresis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " In parallel, GRK4 modulates aspects of the renin–angiotensin system by increasing the expression of angiotensin type 1 receptors in vascular smooth muscle cells via transcriptional mechanisms involving the NF-κB pathway, which contributes to enhanced vasoconstriction and arterial abnormalities."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Numerous genetic studies across different ethnic groups have identified common GRK4 polymorphisms (including R65L, A142V, and A486V) that are associated with essential and salt-sensitive hypertension and also predict differential responses to antihypertensive therapies such as angiotensin receptor blockers and beta blockers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Moreover, GRK4 dysregulation extends beyond the kidney; overexpression or variant forms have been implicated in cardiomyocyte injury during myocardial infarction, where they influence autophagic pathways and apoptosis, thereby contributing to adverse cardiac remodeling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Structural studies have further revealed that the kinase’s autophosphorylation—increased in certain GRK4 variants—may underlie its altered activity, providing a mechanistic basis for the constitutive receptor phosphorylation observed in the absence of agonist stimulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Collectively, these findings highlight GRK4 as a multifaceted regulator whose altered expression or genetic variation disrupts receptor signaling networks critical to sodium excretion and vascular tone, thereby contributing to hypertension and related cardiometabolic disorders.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Pedro A Jose, Patricio Soares-da-Silva, Gilbert M Eisner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dopamine and G protein-coupled receptor kinase 4 in the kidney: role in blood pressure regulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbadis.2010.02.004"}], "href": "https://doi.org/10.1016/j.bbadis.2010.02.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20153824"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20153824"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Michele L Rankin, Paul S Marinec, David M Cabrera, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The D1 dopamine receptor is constitutively phosphorylated by G protein-coupled receptor kinase 4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Pharmacol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1124/mol.105.019901"}], "href": "https://doi.org/10.1124/mol.105.019901"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16338988"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16338988"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Van Anthony M Villar, John E Jones, Ines Armando, et al. "}, {"type": "b", "children": [{"type": "t", "text": "G protein-coupled receptor kinase 4 (GRK4) regulates the phosphorylation and function of the dopamine D3 receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.003665"}], "href": "https://doi.org/10.1074/jbc.M109.003665"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19520868"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19520868"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Ken Chen, Chunjiang Fu, Caiyu Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of GRK4 in the regulation of arterial AT1 receptor in hypertension."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hypertension (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/HYPERTENSIONAHA.113.01766"}], "href": "https://doi.org/10.1161/HYPERTENSIONAHA.113.01766"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24218433"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24218433"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "H Sanada, M Yoneda, J Yatabe, et al. "}, {"type": "b", "children": [{"type": "t", "text": "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."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pharmacogenomics J (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/tpj.2015.6"}], "href": "https://doi.org/10.1038/tpj.2015.6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25732908"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25732908"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Zheng Wang, Ines Armando, Laureano D Asico, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The elevated blood pressure of human GRK4gamma A142V transgenic mice is not associated with increased ROS production."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Heart Circ Physiol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpheart.00944.2006"}], "href": "https://doi.org/10.1152/ajpheart.00944.2006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17259440"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17259440"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Richard G James, Katherine A Bosch, Rima M Kulikauskas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Protein kinase PKN1 represses Wnt/β-catenin signaling in human melanoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.500314"}], "href": "https://doi.org/10.1074/jbc.M113.500314"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24114839"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24114839"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Samantha J Allen, Gopal Parthasarathy, Paul L Darke, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure and Function of the Hypertension Variant A486V of G Protein-coupled Receptor Kinase 4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M115.648907"}], "href": "https://doi.org/10.1074/jbc.M115.648907"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26134571"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26134571"}]}]}]}
Synonyms	GPRK2L, IT11, GPRK4, GRK4A
Proteins	GRK4_HUMAN
NCBI Gene ID	2868
API
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Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

GRK4 has 5,343 functional associations with biological entities spanning 9 categories (molecular profile, organism, functional term, phrase or reference, chemical, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 112 datasets.

Click the + buttons to view associations for GRK4 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

GRK4 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by GRK4 gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of GRK4 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of GRK4 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of GRK4 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of GRK4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of GRK4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of GRK4 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	Biocarta Pathways	pathways involving GRK4 protein from the Biocarta Pathways dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of GRK4 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of GRK4 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of GRK4 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of GRK4 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of GRK4 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of GRK4 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Gene Mutation Profiles	cell lines with GRK4 gene mutations from the CCLE Cell Line Gene Mutation Profiles dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of GRK4 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of GRK4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of GRK4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of GRK4 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing GRK4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing GRK4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing GRK4 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores 2025	cellular components containing GRK4 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with GRK4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with GRK4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of GRK4 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with GRK4 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with GRK4 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with GRK4 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by GRK4 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with GRK4 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with GRK4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with GRK4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with GRK4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with GRK4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at GRK4 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of GRK4 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of GRK4 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing GRK4 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD Gene-Disease Associations	diseases associated with GRK4 gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.