Details for: GRK4

Gene ID: 2868

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: GRK4

Ensembl ID: ENSG00000125388

Description: G protein-coupled receptor kinase 4

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • pvalb GABAergic cortical interneuron CL4023018
    CSI 21.95
    rCSI 27.3%
    PRS 40.83
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 13.79
    rCSI 23.15%
    PRS 42.75
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 13.47
    rCSI 42.12%
    PRS 46.94
  • L6b glutamatergic cortical neuron CL4023038
    CSI 11.37
    rCSI 35.53%
    PRS 44.39
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 11.12
    rCSI 27.03%
    PRS 41.37
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 10.61
    rCSI 38.19%
    PRS 41.17
  • retinal ganglion cell CL0000740
    CSI 7.99
    rCSI 17.66%
    PRS 47.17
  • retinal cone cell CL0000573
    CSI 6.73
    rCSI 10.83%
    PRS 50.52
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 6.71
    rCSI 25.36%
    PRS 43.58
  • megakaryocyte-erythroid progenitor cell CL0000050
    CSI 6.15
    rCSI 5.55%
    PRS 57.71
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 5.42
    rCSI 31.93%
    PRS 44.06
  • interneuron CL0000099
    CSI 5.15
    rCSI 10.33%
    PRS 50.03
  • ON-bipolar cell CL0000749
    CSI 5.02
    rCSI 7.46%
    PRS 62.54
  • cerebral cortex endothelial cell CL1001602
    CSI 4.64
    rCSI 8.02%
    PRS 51.11
  • retinal bipolar neuron CL0000748
    CSI 4.34
    rCSI 8.12%
    PRS 49.34
  • vascular leptomeningeal cell CL4023051
    CSI 4.26
    rCSI 7.47%
    PRS 52.94
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 4.22
    rCSI 7.46%
    PRS 41.84
  • hepatic stellate cell CL0000632
    CSI 4.18
    rCSI 15.67%
    PRS 53.08
  • neuroblast (sensu Vertebrata) CL0000031
    CSI 4.03
    rCSI 5.17%
    PRS 58.09
  • cerebellar granule cell CL0001031
    CSI 4.02
    rCSI 5.91%
    PRS 54.66
  • ependymal cell CL0000065
    CSI 3.98
    rCSI 8.07%
    PRS 40.47
  • sst GABAergic cortical interneuron CL4023017
    CSI 3.95
    rCSI 5.1%
    PRS 44.02
  • L5/6 near-projecting glutamatergic neuron CL4030067
    CSI 3.95
    rCSI 12.99%
    PRS 47.96
  • retinal rod cell CL0000604
    CSI 3.83
    rCSI 6.76%
    PRS 57.9
  • differentiation-committed oligodendrocyte precursor CL4023059
    CSI 3.71
    rCSI 6.75%
    PRS 52.99
  • GABAergic amacrine cell CL4030027
    CSI 3.68
    rCSI 12.6%
    PRS 49.95
  • cardiac muscle cell CL0000746
    CSI 3.65
    rCSI 5.24%
    PRS 50.74
  • inhibitory interneuron CL0000498
    CSI 3.65
    rCSI 8.42%
    PRS 50.09
  • ON parasol ganglion cell CL4033052
    CSI 3.48
    rCSI 49.35%
    PRS 52.23
  • central nervous system neuron CL2000029
    CSI 3.34
    rCSI 24.54%
    PRS 47.69
  • rod bipolar cell CL0000751
    CSI 3.28
    rCSI 5.9%
    PRS 53.98
  • VIP GABAergic cortical interneuron CL4023016
    CSI 3.27
    rCSI 3.91%
    PRS 42.57
  • neuron CL0000540
    CSI 3.19
    rCSI 8.49%
    PRS 50.32
  • kidney connecting tubule epithelial cell CL1000768
    CSI 2.89
    rCSI 7.34%
    PRS 50.39
  • choroid plexus epithelial cell CL0000706
    CSI 2.71
    rCSI 4.44%
    PRS 50.24
  • ON midget ganglion cell CL4033046
    CSI 2.67
    rCSI 54.33%
    PRS 52.02
  • S cone cell CL0003050
    CSI 2.64
    rCSI 11.62%
    PRS 57.72
  • astrocyte of the cerebral cortex CL0002605
    CSI 2.64
    rCSI 5.93%
    PRS 43.51
  • flat midget bipolar cell CL4033033
    CSI 2.58
    rCSI 18.42%
    PRS 54.32
  • Mueller cell CL0000636
    CSI 2.51
    rCSI 5.73%
    PRS 52.77
  • OFF midget ganglion cell CL4033047
    CSI 2.48
    rCSI 50.55%
    PRS 53.29
  • neural crest cell CL0011012
    CSI 2.42
    rCSI 1.91%
    PRS 47.81
  • Bergmann glial cell CL0000644
    CSI 2.42
    rCSI 3.31%
    PRS 54.6
  • chondrocyte CL0000138
    CSI 2.42
    rCSI 3.84%
    PRS 53.27
  • sncg GABAergic cortical interneuron CL4023015
    CSI 2.4
    rCSI 3.85%
    PRS 44.81
  • OFF-bipolar cell CL0000750
    CSI 2.18
    rCSI 2.98%
    PRS 68.04
  • extravillous trophoblast CL0008036
    CSI 2.01
    rCSI 2.49%
    PRS 57.38
  • neural progenitor cell CL0011020
    CSI 2.01
    rCSI 8.82%
    PRS 51.46
  • GABAergic neuron CL0000617
    CSI 1.91
    rCSI 6.41%
    PRS 46.19
  • glutamatergic neuron CL0000679
    CSI 1.89
    rCSI 3.89%
    PRS 51.47
  • regular atrial cardiac myocyte CL0002129
    CSI 1.87
    rCSI 6.02%
    PRS 59.31
  • direct pathway medium spiny neuron CL4023026
    CSI 1.81
    rCSI 43.31%
    PRS 41.82
  • indirect pathway medium spiny neuron CL4023029
    CSI 1.79
    rCSI 43.11%
    PRS 42.74
  • glycinergic amacrine cell CL4030028
    CSI 1.78
    rCSI 4.63%
    PRS 58.55
  • retinal pigment epithelial cell CL0002586
    CSI 1.66
    rCSI 3.31%
    PRS 58.73
  • L2/3 intratelencephalic projecting glutamatergic neuron CL4030059
    CSI 1.52
    rCSI 3.3%
    PRS 48.99
  • regular ventricular cardiac myocyte CL0002131
    CSI 1.12
    rCSI 7.01%
    PRS 52.84
  • OFFx cell CL4033036
    CSI 1.02
    rCSI 4.81%
    PRS 55.86
  • diffuse bipolar 6 cell CL4033032
    CSI 0.95
    rCSI 4.97%
    PRS 55.47
  • L4 intratelencephalic projecting glutamatergic neuron CL4030063
    CSI 0.94
    rCSI 2.26%
    PRS 48.29
  • medium spiny neuron CL1001474
    CSI 0.91
    rCSI 7.82%
    PRS 48.36
  • amacrine cell CL0000561
    CSI 0.85
    rCSI 2.47%
    PRS 50.61
  • macroglial cell CL0000126
    CSI 0.8
    rCSI 2.06%
    PRS 60.78
  • diffuse bipolar 3a cell CL4033029
    CSI 0.61
    rCSI 4.13%
    PRS 56.82
  • diffuse bipolar 3b cell CL4033030
    CSI 0.6
    rCSI 3.95%
    PRS 58.24
  • GABAergic interneuron CL0011005
    CSI 0.34
    rCSI 5.39%
    PRS 65.99

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [GRK4](/details-gene/2868) (G protein-coupled receptor kinase 4) is a protein-coding gene located on chromosome 4p16.3 that encodes a member of the G protein-coupled receptor kinase (GRK) subfamily. Its primary function involves the phosphorylation of G protein-coupled receptors (GPCRs), a key mechanism for receptor desensitization, internalization, and regulation of downstream signaling pathways ([GO:0008277](https://www.ebi.ac.uk/QuickGO/term/GO:0008277), [GO:0006468](https://www.ebi.ac.uk/QuickGO/term/GO:0006468)). Expression data highlights its significant role within the central nervous system. **Overall**, [GRK4](/details-gene/2868) shows particularly high significance in various neuronal subtypes, including [pvalb GABAergic cortical interneurons](/details-cell/CL4023018) (CSI: 21.95), [lamp5 GABAergic cortical interneurons](/details-cell/CL4023011) (CSI: 13.79), and multiple glutamatergic cortical neurons. Its established role in visual phototransduction is supported by its expression in [retinal ganglion cells](/details-cell/CL0000740) and [retinal cone cells](/details-cell/CL0000573). Polymorphisms in [GRK4](/details-gene/2868) have been associated with essential hypertension ([137026](https://omim.org/entry/137026)). ## Cellular Roles and Expression Landscape The expression profile of [GRK4](/details-gene/2868) strongly points to a specialized function in the nervous system, particularly in modulating neuronal excitability and sensory perception. The **Overall** context reveals its highest significance in cortical neurons, positioning it as a key regulator of cortical microcircuits. The top-ranked cell types are dominated by inhibitory interneurons such as [pvalb GABAergic cortical interneurons](/details-cell/CL4023018) and [chandelier pvalb GABAergic cortical interneurons](/details-cell/CL4023036), as well as excitatory neurons including [L6b glutamatergic cortical neurons](/details-cell/CL4023038) and [L5 extratelencephalic projecting glutamatergic cortical neurons](/details-cell/CL4023041). This suggests a broad role in fine-tuning signal transduction across different neuronal populations in the cerebral cortex. Furthermore, its significant expression in specialized sensory neurons, such as [retinal cone cells](/details-cell/CL0000573) and [ON-bipolar cells](/details-cell/CL0000749), is highly consistent with its well-defined role in the visual phototransduction cascade. The absence of major immune, epithelial, or stromal cell types in the high-significance list underscores its specific role within neuronal and neuro-sensory tissues. While not a top-ranked cell type in this dataset, literature also highlights its importance in spermatozoa and germinal cells ([Link](https://doi.org/10.1074/jbc.272.15.10188)) and in the kidney, where it regulates dopamine receptor function and sodium transport ([Link](https://doi.org/10.1161/01.hyp.0000222004.74872.17)). ## Pathways and Molecular Function [GRK4](/details-gene/2868) is a serine/threonine protein kinase ([GO:0004672](https://www.ebi.ac.uk/QuickGO/term/GO:0004672)) that functions by binding ATP ([GO:0005524](https://www.ebi.ac.uk/QuickGO/term/GO:0005524)) and phosphorylating agonist-occupied GPCRs. This action facilitates the binding of arrestin proteins, which uncouple the receptor from its G protein, thereby terminating the signal and often targeting the receptor for internalization ([GO:0031623](https://www.ebi.ac.uk/QuickGO/term/GO:0031623)). Its functional annotation is strongly linked to its cellular expression pattern. The Reactome pathway 'Visual phototransduction' ([R-HSA-2187338](https://reactome.org/content/detail/R-HSA-2187338)) directly corresponds to its activity as a rhodopsin kinase ([GO:0050254](https://www.ebi.ac.uk/QuickGO/term/GO:0050254)) in retinal cells, where it is essential for the recovery phase of the visual cycle. In cortical neurons, its general role in regulating GPCR signaling ([GO:0008277](https://www.ebi.ac.uk/QuickGO/term/GO:0008277)) is critical for modulating the cellular response to numerous neurotransmitters, including dopamine, as it has been shown to directly phosphorylate and regulate the dopamine D3 receptor ([Link](https://doi.org/10.1074/jbc.m109.003665)). This function likely underlies its high significance in both GABAergic and glutamatergic neurons, which rely on precise GPCR-mediated neuromodulation. ## Research Directions Based on its specific expression pattern and known molecular functions, several research avenues can be proposed to further elucidate the role of [GRK4](/details-gene/2868) in health and disease. **Proposed Hypotheses:** 1. Given its high significance in [pvalb GABAergic cortical interneurons](/details-cell/CL4023018) and its documented ability to regulate dopamine D3 receptors ([Link](https://doi.org/10.1074/jbc.m109.003665)), [GRK4](/details-gene/2868) may be a critical modulator of cortical network oscillations (e.g., gamma oscillations) that are governed by these interneurons and are crucial for cognitive processes. Dysregulation of [GRK4](/details-gene/2868) in this context could contribute to cognitive deficits seen in neuropsychiatric disorders like schizophrenia. 2. Genetic variants of [GRK4](/details-gene/2868) associated with hypertension ([Link](https://doi.org/10.1161/01.hyp.0000222004.74872.17)) likely lead to gain-of-function activity, resulting in excessive desensitization of renal dopamine D1 receptors. This would impair dopamine-mediated sodium excretion, leading to sodium retention and a salt-sensitive hypertensive phenotype. **Experimental Approach:** To test the first hypothesis regarding the role of [GRK4](/details-gene/2868) in cortical interneuron function, a conditional knockout mouse model could be generated by crossing Pvalb-Cre driver mice with GRK4-floxed mice. This would specifically delete [GRK4](/details-gene/2868) in parvalbumin-expressing interneurons. *Ex vivo* electrophysiological recordings from cortical slices could then be used to measure changes in gamma oscillations and the response of these neurons to dopamine receptor agonists. Complementary behavioral assays, such as the pre-pulse inhibition test or novel object recognition test, would assess for schizophrenia-relevant cognitive and sensory gating deficits. **Therapeutic Potential:** [GRK4](/details-gene/2868) presents a compelling, albeit challenging, therapeutic target. For hypertension, the therapeutic strategy would be **inhibition**. The development of selective small molecule inhibitors targeting the kinase activity of [GRK4](/details-gene/2868) could restore normal dopamine receptor signaling in the kidney and promote natriuresis. The primary challenge would be designing inhibitors with high specificity for [GRK4](/details-gene/2868) over other GRK family members and achieving targeted delivery to the kidney to avoid potential neurological side effects, given its high expression in the brain.

Genular Protein ID: 8148966

Symbol: GRK4_HUMAN

Name: G protein-coupled receptor kinase 4

UniProtKB Accession Codes:

P32298 O00641 O00642 Q13293 Q13294 Q13295 Q14453 Q14725 Q15313 Q15314 Q15315 Q15316 Q17RH6 Q53EQ8

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 4 CDD 1 CTD 1 ChEBI 7 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugCentral 1 EC 2 EMBL 72 Ensembl 4 EvolutionaryTrace 1 ExpressionAtlas 1 GO 13 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 9 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 1 PDBsum 1 PIR 2 PRINTS 1 PRO 1 PROSITE 5 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 4 RNAct 1 Reactome 1 RefSeq 4 Rhea 3 SIGNOR 1 SMART 3 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 1338872

Title: A novel G protein-coupled receptor kinase gene cloned from 4p16.3.

PubMed ID: 1338872

DOI: 10.1093/hmg/1.9.697

PubMed ID: 9092566

Title: G protein-coupled receptor kinase GRK4. Molecular analysis of the four isoforms and ultrastructural localization in spermatozoa and germinal cells.

PubMed ID: 9092566

DOI: 10.1074/jbc.272.15.10188

PubMed ID: 8626439

Title: Characterization of the G protein-coupled receptor kinase GRK4. Identification of four splice variants.

PubMed ID: 8626439

DOI: 10.1074/jbc.271.11.6403

PubMed ID: 8135832

Title: Two isoforms of G protein-coupled receptor kinase 4 identified by molecular cloning.

PubMed ID: 8135832

DOI: 10.1006/bbrc.1994.1306

PubMed ID: 15815621

Title: Generation and annotation of the DNA sequences of human chromosomes 2 and 4.

PubMed ID: 15815621

DOI: 10.1038/nature03466

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 16636192

Title: Amelioration of genetic hypertension by suppression of renal G protein-coupled receptor kinase type 4 expression.

PubMed ID: 16636192

DOI: 10.1161/01.hyp.0000222004.74872.17

PubMed ID: 19520868

Title: G protein-coupled receptor kinase 4 (GRK4) regulates the phosphorylation and function of the dopamine D3 receptor.

PubMed ID: 19520868

DOI: 10.1074/jbc.m109.003665

PubMed ID: 22223895

Title: Comparative large-scale characterisation of plant vs. mammal proteins reveals similar and idiosyncratic N-alpha acetylation features.

PubMed ID: 22223895

DOI: 10.1074/mcp.m111.015131

PubMed ID: 17344846

Title: Patterns of somatic mutation in human cancer genomes.

PubMed ID: 17344846

DOI: 10.1038/nature05610

Sequence Information:

  • Length: 578
  • Mass: 66583
  • Checksum: 72FCF94ED551F2D0
  • Sequence:
    • MELENIVANS LLLKARQGGY GKKSGRSKKW KEILTLPPVS QCSELRHSIE KDYSSLCDKQ 
PIGRRLFRQF CDTKPTLKRH IEFLDAVAEY EVADDEDRSD CGLSILDRFF NDKLAAPLPE 
IPPDVVTECR LGLKEENPSK KAFEECTRVA HNYLRGEPFE EYQESSYFSQ FLQWKWLERQ 
PVTKNTFRHY RVLGKGGFGE VCACQVRATG KMYACKKLQK KRIKKRKGEA MALNEKRILE 
KVQSRFVVSL AYAYETKDAL CLVLTIMNGG DLKFHIYNLG NPGFDEQRAV FYAAELCCGL 
EDLQRERIVY RDLKPENILL DDRGHIRISD LGLATEIPEG QRVRGRVGTV GYMAPEVVNN 
EKYTFSPDWW GLGCLIYEMI QGHSPFKKYK EKVKWEEVDQ RIKNDTEEYS EKFSEDAKSI 
CRMLLTKNPS KRLGCRGEGA AGVKQHPVFK DINFRRLEAN MLEPPFCPDP HAVYCKDVLD 
IEQFSVVKGI YLDTADEDFY ARFATGCVSI PWQNEMIESG CFKDINKSES EEALPLDLDK 
NIHTPVSRPN RGFFYRLFRR GGCLTMVPSE KEVEPKQC