GRK6

Last updated
GRK6
Protein GRK6 PDB 2acx.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases GRK6 , GPRK6, G protein-coupled receptor kinase 6
External IDs OMIM: 600869 MGI: 1347078 HomoloGene: 37570 GeneCards: GRK6
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001004105
NM_001004106
NM_002082
NM_001364164

RefSeq (protein)

NP_001004105
NP_001004106
NP_002073
NP_001351093

Location (UCSC) Chr 5: 177.4 – 177.44 Mb Chr 13: 55.59 – 55.61 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.

Contents

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]

Related Research Articles

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<span class="mw-page-title-main">Arrestin</span> Family of proteins

Arrestins are a small family of proteins important for regulating signal transduction at G protein-coupled receptors. Arrestins were first discovered as a part of a conserved two-step mechanism for regulating the activity of G protein-coupled receptors (GPCRs) in the visual rhodopsin system by Hermann Kühn, Scott Hall, and Ursula Wilden and in the β-adrenergic system by Martin J. Lohse and co-workers.

<span class="mw-page-title-main">G protein-coupled receptor kinase</span>

G protein-coupled receptor kinases are a family of protein kinases within the AGC group of kinases. Like all AGC kinases, GRKs use ATP to add phosphate to Serine and Threonine residues in specific locations of target proteins. In particular, GRKs phosphorylate intracellular domains of G protein-coupled receptors (GPCRs). GRKs function in tandem with arrestin proteins to regulate the sensitivity of GPCRs for stimulating downstream heterotrimeric G protein and G protein-independent signaling pathways.

<span class="mw-page-title-main">G protein-coupled receptor kinase 2</span> Enzyme

G-protein-coupled receptor kinase 2 (GRK2) is an enzyme that in humans is encoded by the ADRBK1 gene. GRK2 was initially called Beta-adrenergic receptor kinase, and is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases that is most highly similar to GRK3(βARK2).

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<span class="mw-page-title-main">AKT1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Alpha-1B adrenergic receptor</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Arrestin beta 2</span> Protein-coding gene in the species Homo sapiens

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In enzymology, a beta-adrenergic-receptor kinase is an enzyme that catalyzes the chemical reaction:

<span class="mw-page-title-main">Arrestin beta 1</span> Human protein and coding gene

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<span class="mw-page-title-main">Protein kinase D1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">GIT1</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">CYTH2</span> Protein-coding gene in the species Homo sapiens

Cytohesin-2 is a protein that in humans is encoded by the CYTH2 gene.

<span class="mw-page-title-main">GRK5</span> Protein-coding gene in the species Homo sapiens

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. The protein phosphorylates the activated forms of G protein-coupled receptors to regulate their signaling.

<span class="mw-page-title-main">GRK4</span> Protein-coding gene in the species Homo sapiens

G protein-coupled receptor kinase 4 (GRK4) is an enzyme that is encoded by the GRK4 gene in humans.

<span class="mw-page-title-main">ARR3</span> Protein-coding gene in humans

Arrestin-C, also known as retinal cone arrestin-3, is a protein that in humans is encoded by the ARR3 gene.

<span class="mw-page-title-main">DVL2</span> Human protein and coding gene

Segment polarity protein dishevelled homolog DVL-2 is a protein that in humans is encoded by the DVL2 gene.

<span class="mw-page-title-main">G protein-coupled receptor kinase 3</span> Protein-coding gene in the species Homo sapiens

G-protein-coupled receptor kinase 3 (GRK3) is an enzyme that in humans is encoded by the ADRBK2 gene. GRK3 was initially called Beta-adrenergic receptor kinase 2 (βARK-2), and is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases that is most highly similar to GRK2.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000198055 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000074886 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Benovic JL, Gomez J (1993). "Molecular cloning and expression of GRK6. A new member of the G protein-coupled receptor kinase family". J Biol Chem. 268 (26): 19521–19527. doi: 10.1016/S0021-9258(19)36546-9 . PMID   8366096.
  6. 1 2 Haribabu B, Snyderman R (1993). "Identification of additional members of human G-protein-coupled receptor kinase multigene family". Proc Natl Acad Sci USA. 90 (20): 9398–9402. Bibcode:1993PNAS...90.9398H. doi: 10.1073/pnas.90.20.9398 . PMC   47575 . PMID   8415712.
  7. Premont RT, Inglese J, Lefkowitz RJ (1995). "Protein kinases that phosphorylate activated G protein-coupled receptors". FASEB J. 9 (2): 175–182. doi: 10.1096/fasebj.9.2.7781920 . PMID   7781920. S2CID   20428064.
  8. Gurevich VV, Gurevich EV (2019). "GPCR Signaling Regulation: The Role of GRKs and Arrestins". Front Pharmacol. 10: 125. doi: 10.3389/fphar.2019.00125 . PMC   6389790 . PMID   30837883.
  9. Kim J, Ahn S, Ren XR, Whalen EJ, Reiter E, Wei H, Lefkowitz RJ (2005). "Functional antagonism of different G protein-coupled receptor kinases for beta-arrestin-mediated angiotensin II receptor signaling". Proc Natl Acad Sci USA. 102 (5): 1442–1447. Bibcode:2005PNAS..102.1442K. doi: 10.1073/pnas.0409532102 . PMC   547874 . PMID   15671181.
  10. Ren XR, Reiter E, Ahn S, Kim J, Chen W, Lefkowitz RJ (2005). "Different G protein-coupled receptor kinases govern G protein and beta-arrestin-mediated signaling of V2 vasopressin receptor". Proc Natl Acad Sci USA. 102 (5): 1448–1453. Bibcode:2005PNAS..102.1448R. doi: 10.1073/pnas.0409534102 . PMC   547876 . PMID   15671180.
  11. Zidar DA, Violin JD, Whalen EJ, Lefkowitz RJ (2009). "Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands". Proc Natl Acad Sci USA. 106 (24): 9649–9654. Bibcode:2009PNAS..106.9649Z. doi: 10.1073/pnas.0904361106 . PMC   2689814 . PMID   19497875.
  12. Choi M, Staus DP, Wingler LM, Ahn S, Pani B, Capel WD, Lefkowitz RJ (2018). "G protein-coupled receptor kinases (GRKs) orchestrate biased agonism at the β2-adrenergic receptor". Sci Signal. 11 (544): eaar7084. doi: 10.1126/scisignal.aar7084 . PMID   30131371.
  13. Premont RT, Macrae AD, Aparicio SA, Kendall HE, Welch JE, Lefkowitz RJ (1999). "The GRK4 subfamily of G protein-coupled receptor kinases. Alternative splicing, gene organization, and sequence conservation". J Biol Chem. 274 (41): 29381–29389. doi: 10.1074/jbc.274.41.29381 . PMID   10506199.
  14. Gainetdinov RR, Bohn LM, Sotnikova TD, Cyr M, Laakso A, Macrae AD, Torres GE, Kim KM, Lefkowitz RJ, Caron MG, Premont RT (2003). "Dopaminergic supersensitivity in G protein-coupled receptor kinase 6-deficient mice". Neuron. 38 (2): 291–303. doi: 10.1016/S0896-6273(03)00192-2 . PMID   12718862. S2CID   13986538.
  15. Ahmed MR, Berthet A, Bychkov E, Porras G, Li Q, Bioulac BH, Carl YT, Bloch B, Kook S, Aubert I, Dovero S, Doudnikoff E, Gurevich VV, Gurevich EV, Bezard E (2010). "Lentiviral overexpression of GRK6 alleviates L-dopa-induced dyskinesia in experimental Parkinson's disease". Sci Transl Med. 2 (28): 28ra28. doi:10.1126/scitranslmed.3000664. PMC   2933751 . PMID   20410529.
  16. Fong AM, Premont RT, Richardson RM, Yu YR, Lefkowitz RJ, Patel DD (2002). "Defective lymphocyte chemotaxis in beta-arrestin2- and GRK6-deficient mice". Proc Natl Acad Sci USA. 99 (11): 7478–7483. Bibcode:2002PNAS...99.7478F. doi: 10.1073/pnas.112198299 . PMC   124256 . PMID   12032308.
  17. Kavelaars A, Vroon A, Raatgever RP, Fong AM, Premont RT, Patel DD, Lefkowitz RJ, Heijnen CJ (2003). "Increased acute inflammation, leukotriene B4-induced chemotaxis, and signaling in mice deficient for G protein-coupled receptor kinase 6". J Immunol. 171 (11): 6128–6134. doi: 10.4049/jimmunol.171.11.6128 . PMID   14634128.

Further reading