GRK6

GRK6
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2ACX, 3NYN, 3NYO
Identifiers
Aliases	GRK6, GPRK6, G protein-coupled receptor kinase 6
External IDs	OMIM: 600869; MGI: 1347078; HomoloGene: 37570; GeneCards: GRK6; OMA:GRK6 - orthologs
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5q35.3 Start 177,403,204 bp[1] End 177,442,901 bp[1]
Gene location (Mouse) Chr. Chromosome 13 (mouse)[2] Band 13 B1|13 30.06 cM Start 55,592,885 bp[2] End 55,608,740 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in blood monocyte bone marrow cells lymph node spleen appendix pancreatic ductal cell sperm thymus olfactory bulb Top expressed in Paneth cell internal carotid artery condyle fossa external carotid artery blood spleen substantia nigra vas deferens primitive streak More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity nucleotide binding protein kinase activity protein serine/threonine kinase activity protein binding ATP binding G protein-coupled receptor kinase activity kinase activity beta-adrenergic receptor kinase activity Cellular component membrane plasma membrane Biological process protein phosphorylation Wnt signaling pathway phosphorylation regulation of G protein-coupled receptor signaling pathway signal transduction G protein-coupled receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2870 26385 Ensembl ENSG00000198055 ENSMUSG00000074886 UniProt P43250 O70293 RefSeq (mRNA) NM_001004105 NM_001004106 NM_002082 NM_001364164 NM_001038018 NM_001112711 NM_001286063 NM_001286064 NM_001286065 NM_001286066 NM_011938 NM_001377076 NM_001377077 RefSeq (protein) NP_001004105 NP_001004106 NP_002073 NP_001351093 NP_001033107 NP_001106182 NP_001272992 NP_001272993 NP_001272994 NP_001272995 NP_036068 NP_001364005 NP_001364006 Location (UCSC) Chr 5: 177.4 – 177.44 Mb Chr 13: 55.59 – 55.61 Mb PubMed search [3] [4]
Wikidata
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This gene encodes a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinase family, and is most highly similar to GRK4 and GRK5.^[5][6][7] The protein phosphorylates the activated forms of G protein-coupled receptors to regulate their signaling.

Function

G protein-coupled receptor kinases phosphorylate activated G protein-coupled receptors, which promotes the binding of an arrestin protein to the receptor. Arrestin binding to phosphorylated, active receptor prevents receptor stimulation of heterotrimeric G protein transducer proteins, blocking their cellular signaling and resulting in receptor desensitization. Arrestin binding also directs receptors to specific cellular internalization pathways, removing the receptors from the cell surface and also preventing additional activation. Arrestin binding to phosphorylated, active receptor also enables receptor signaling through arrestin partner proteins. Thus the GRK/arrestin system serves as a complex signaling switch for G protein-coupled receptors.^[8]

GRK6 and the closely related GRK5 phosphorylate receptors at sites that encourage arrestin-mediated signaling rather than arrestin-mediated receptor desensitization, internalization and trafficking (in contrast to GRK2 and GRK3, which have the opposite effect).^[9][10] This difference is one basis for pharmacological biased agonism (also called functional selectivity), where a drug binding to a receptor may bias that receptor's signaling toward a particular subset of the actions stimulated by that receptor.^[11][12]

GRK6 is widely and relatively evenly expressed throughout the body, but with particularly high expression in immune cells.^[6] GRK6 exists in three splice variants that differ in the carboxyl terminal region that regulates membrane association: one form is palmitoylated, another contains a lipid-binding polybasic domain, and the third is truncated and has neither.^[13] In the mouse, GRK6 regulates the D2 dopamine receptor in the striatum region of the brain, and loss of GRK6 leads to increased sensitivity to psychostimulant drugs that act through dopamine.^[14] Overexpression of GRK6 in the striatum in a rat model of Parkinson's disease improves drug-induced movement disorder (tardive dyskinesia) symptoms arising from L-DOPA therapy.^[15] In mouse immune cells, GRK6 is important for chemotaxis of B-lymphocytes and T-lymphocytes in response to the chemoattractant CXCL12,^[16] and of neutrophils to sites of injury in response to leukotriene B4.^[17]

References

Further reading

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