The Role of G Protein-Coupled Receptor Kinase 6 Regulation in Inflammation and Pain
Abstract
:1. G Protein-Coupled Receptor Kinases
2. Characteristics of G Protein-Coupled Receptor Kinase 6
3. GRK6 in the Clinical Setting of Inflammation and Inflammatory Hyperalgesia
4. GRK6-Knockout Studies Addressing Inflammation and Hyperalgesia
5. GRK6 in Autoimmunity
6. The Potential Role of GRK6 in Chemotaxis
Receptor | Main G Protein Coupled | Main Ligand | Main Signaling Pathways Induced | Impact of GRK6 |
---|---|---|---|---|
calcitonin gene-related peptide receptor (CGRP-R) | Gs Gi/o Gaq/11 | calcitonin gene-related peptide (CGRP) | - activation of cAMP production via adenylate cyclase - calcium mobilisation via phospholipase C β [80] | GRK6 is involved in receptor downregulation [79] |
C-C receptor 7 (CCR7) | Gi | CCL19 > CCL21 | - inhibition of cAMP production - β arrestin- mediated MAP kinase signaling [81] | GRK6 deficiency impairs β arrestin recruitment to CCR7 [73] |
chemokine-like receptor 1 (CMKLR1) | Gi Go | chemerin resolvin E1 | - calcium mobilisation via phospholipase C β - inhibition of cAMP production - MAP kinase signaling - phosphatidylinositol 3- kinase (PI3K) signaling [82] | GRK6- and β arrestin 2-deficiency leads to increased migration upon chemerin binding [74] GRK6 deficiency leads to increased Akt phosphorylation upon chemerin binding [74] |
C-X-C receptor type 4 (CXCR4) | Gi | CXCL12 (also titled SDF1α) | - extracellular signal-related kinases (ERK) 1/2 | mutation of CXCR4 leads to impaired receptor silencing inter alia by GRK6 and results in WHIM syndrome (papilloma-virus induced warts, hypogammaglobulinemia, bacterial infection, myelokathexis) [66] GRK6-deficiency leads to impaired chemotaxis and transepithelial migration in B and T lymphocytes [67] GRK6-deficient neutrophils showed enhanced chemotaxis but reduced mobilisation from the bone marrow to the peripheral blood circulation [68] |
leukotriene B4 receptor 1 (BLT1) | Gi [83] | leukotriene B4 | - activation of phospholipase C β via the Gβγ subunit, Ras, PI3K [84] | GRK6 deficiency promotes increased chemotactic activity in neutrophils and leads to an increased inflammatory reaction in response to arachidonic acid [72] |
platelet- derived growth factor β receptor (PDGF-R) | tyrosine kinase receptor | platelet-derived growth factor | - MAP kinase signaling [85] - phospholipase C γ [85] - phosphatidyl- inositol 3-kinase [85] | activation of PDGF-R is associated with decreased GRK6 expression [86] |
7. GRK6 in the Context of Transcriptional Regulation Mediated by NFκB
8. GRK6 Contributes to Reduced Hypoxia-Induced Factor 1-α Activity
9. GRK6 as a Potential Therapeutic Target in Treating Chronic Inflammatory Diseases
10. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Stegen, M.; Frey, U.H. The Role of G Protein-Coupled Receptor Kinase 6 Regulation in Inflammation and Pain. Int. J. Mol. Sci. 2022, 23, 15880. https://doi.org/10.3390/ijms232415880
Stegen M, Frey UH. The Role of G Protein-Coupled Receptor Kinase 6 Regulation in Inflammation and Pain. International Journal of Molecular Sciences. 2022; 23(24):15880. https://doi.org/10.3390/ijms232415880
Chicago/Turabian StyleStegen, Maike, and Ulrich H. Frey. 2022. "The Role of G Protein-Coupled Receptor Kinase 6 Regulation in Inflammation and Pain" International Journal of Molecular Sciences 23, no. 24: 15880. https://doi.org/10.3390/ijms232415880