GRK5

GRK5
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4TNB, 4TND
Identifiers
Aliases	GRK5, GPRK5, G protein-coupled receptor kinase 5, FP2025
External IDs	OMIM: 600870; MGI: 109161; HomoloGene: 3879; GeneCards: GRK5; OMA:GRK5 - orthologs
Gene location (Human) Chr. Chromosome 10 (human)[1] Band 10q26.11 Start 119,207,571 bp[1] End 119,459,745 bp[1]
Gene location (Mouse) Chr. Chromosome 19 (mouse)[2] Band 19 D3|19 56.52 cM Start 60,878,187 bp[2] End 61,084,406 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in saphenous vein pylorus synovial joint cardia lower lobe of lung pericardium jejunal mucosa synovial membrane urethra right lung Top expressed in blood zygote granulocyte tail of embryo secondary oocyte Gonadal ridge genital tubercle myocardium of ventricle esophagus morula More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity nucleotide binding protein kinase activity G protein-coupled receptor kinase activity kinase activity protein serine/threonine kinase activity protein binding phospholipid binding ATP binding protein kinase C binding lipid binding beta-adrenergic receptor kinase activity Cellular component nuclear membrane membrane plasma membrane nucleus cytoplasm cytosol nuclear speck Biological process phosphorylation adenylate cyclase-modulating G protein-coupled receptor signaling pathway negative regulation of apoptotic process Wnt signaling pathway tachykinin receptor signaling pathway regulation of cell cycle protein phosphorylation positive regulation of cell population proliferation protein autophosphorylation fat cell differentiation signal transduction apoptotic process regulation of G protein-coupled receptor signaling pathway G protein-coupled receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2869 14773 Ensembl ENSG00000198873 ENSMUSG00000003228 UniProt P34947 Q8VEB1 RefSeq (mRNA) NM_005308 NM_018869 RefSeq (protein) NP_005299 NP_061357 Location (UCSC) Chr 10: 119.21 – 119.46 Mb Chr 19: 60.88 – 61.08 Mb PubMed search [3] [4]
Wikidata
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G protein-coupled receptor kinase 5 is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases, and is most highly similar to GRK4 and GRK6.^[5][6][7] The protein phosphorylates the activated forms of G protein-coupled receptors to regulate their signaling.

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]

GRK5 and the closely related GRK6 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]

GRK5 is widely expressed throughout the body, but with notably high expression in the lung, heart and placenta, with widespread expression at lower levels.^[13] In humans, a GRK5 sequence polymorphism at residue 41 (leucine rather than glutamine) that is most common in individuals with African ancestry leads to elevated GRK5-mediated desensitization of airway beta2-adrenergic receptors, a drug target in asthma.^[14] In the mouse, GRK5 regulates the M2 subtype of Muscarinic acetylcholine receptors in airways and neurons, and mice lacking GRK5 have been proposed as a model for Alzheimer's disease.^[15][16][17] In zebrafish and in humans, loss of GRK5 function has been associated with heart defects due to heterotaxy, a series of developmental defects arising from improper left-right laterality during organogenesis.^[18] Overexpression of GRK5 in the heart of mice has shown that GRK5 regulates beta2-adrenergic receptors, but GRK5 overexpression or deletion does not affect signaling by the angiotensin II AT1 receptor in the heart.^[19][20]

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