CMKLR1 explained

Chemokine like receptor 1 also known as ChemR23 (Chemerin Receptor 23) is a protein that in humans is encoded by the CMKLR1 gene.^{[1] [2]} Chemokine receptor-like 1 is a G protein-coupled receptor for the chemoattractant adipokine chemerin^[3] and the omega-3 fatty acid eicosapentaenoic acid-derived specialized pro-resolving molecule, resolvin E1 (see Specialized proresolving mediators#EPA-derived resolvins (i.e. RvE)).^[4] The murine receptor that shares almost 80% homology with the human receptor, is called Dez.^[5]

Tissue distribution

CMKLR1 shows wide RNA expression profile but is notably high in plasmacytoid dendritic cells, macrophages, cardiomyocytes, adipocytes and endothelial cells.^[6]

Function

Activating CMKLR1 by an agonist mobilizes intracellular calcium and causes the activation of several other signaling cascades like the ERK1 and NF-κB. Initial studies of CMKLR1 suggested that it might have a role in the inflammatory pathways. Its cognate ligand, chemerin was found in joint aspirate from rheumatoid arthritis and absent in aspirate from degenerative arthritis. CMKLR1 expression by plasmacytoid dendritic cells and macrophages also helped foster this idea. In vitro chemotaxis assays showed it to be utilized in attracting these cells. As an adipokine receptor it has a role in adipogenesis and adipocyte maturation.^[7] It seems also to have a role in peripheral insulin resistance.^[8]

Also studies using the mouse zymosan model and chemerin peptides showed that these peptides suppressed and helped resolve the peritonitis in mice.^[9] The same model showed that this particular molecule enhances macrophage efferocytosis (phagocyting apoptotic cells).^[10]

Receptor antagonist CCX832

CCX832 is an orally active molecule used as a tool compound in experimental pharmacology. It antagonises the effect of CMKLR1.^{[11] [12] [13]} It is listed on the Guide to Pharmacology database as the only example of a CMKLR1 antagonist. Its chemical structure is undisclosed.^[14]

The substance was originally developed for use as a pharmaceutical drug against inflammatory diseases by ChemoCentryx, a pharmaceutical firm based in California, in alliance with GlaxoSmithKline (GSK).^[15] Development was terminated after a Phase I clinical trial in 2012.^[16]

Further reading

• Owman C, Lolait SJ, Santén S, Olde B . Molecular cloning and tissue distribution of cDNA encoding a novel chemoattractant-like receptor . Biochemical and Biophysical Research Communications . 241 . 2 . 390–4 . December 1997 . 9425281 . 10.1006/bbrc.1997.7822 .
• Samson M, Edinger AL, Stordeur P, Rucker J, Verhasselt V, Sharron M, Govaerts C, Mollereau C, Vassart G, Doms RW, Parmentier M . ChemR23, a putative chemoattractant receptor, is expressed in monocyte-derived dendritic cells and macrophages and is a coreceptor for SIV and some primary HIV-1 strains . European Journal of Immunology . 28 . 5 . 1689–700 . May 1998 . 9603476 . 10.1002/(SICI)1521-4141(199805)28:05<1689::AID-IMMU1689>3.0.CO;2-I . free .
• Hillman RT, Green RE, Brenner SE . An unappreciated role for RNA surveillance . Genome Biology . 5 . 2 . R8 . 2005 . 14759258 . 395752 . 10.1186/gb-2004-5-2-r8 . free .
• Mårtensson UE, Fenyö EM, Olde B, Owman C . Characterization of the human chemerin receptor--ChemR23/CMKLR1--as co-receptor for human and simian immunodeficiency virus infection, and identification of virus-binding receptor domains . Virology . 355 . 1 . 6–17 . November 2006 . 16904155 . 10.1016/j.virol.2006.07.010 . free .

Notes and References

1. Web site: Entrez Gene: CMKLR1 chemokine-like receptor 1.
2. Gantz I, Konda Y, Yang YK, Miller DE, Dierick HA, Yamada T . Molecular cloning of a novel receptor (CMKLR1) with homology to the chemotactic factor receptors . Cytogenetics and Cell Genetics . 74 . 4 . 286–90 . 1996 . 8976386 . 10.1159/000134436 .
3. Wittamer V, Franssen JD, Vulcano M, Mirjolet JF, Le Poul E, Migeotte I, Brézillon S, Tyldesley R, Blanpain C, Detheux M, Mantovani A, Sozzani S, Vassart G, Parmentier M, Communi D . Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids . The Journal of Experimental Medicine . 198 . 7 . 977–85 . October 2003 . 14530373 . 2194212 . 10.1084/jem.20030382 .
4. Arita M, Bianchini F, Aliberti J, Sher A, Chiang N, Hong S, Yang R, Petasis NA, Serhan CN . Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1 . The Journal of Experimental Medicine . 201 . 5 . 713–22 . March 2005 . 15753205 . 2212834 . 10.1084/jem.20042031 .
5. Methner A, Hermey G, Schinke B, Hermans-Borgmeyer I . A novel G protein-coupled receptor with homology to neuropeptide and chemoattractant receptors expressed during bone development . Biochemical and Biophysical Research Communications . 233 . 2 . 336–42 . April 1997 . 9144535 . 10.1006/bbrc.1997.6455 .
6. Kaur J, Adya R, Tan BK, Chen J, Randeva HS . Identification of chemerin receptor (ChemR23) in human endothelial cells: chemerin-induced endothelial angiogenesis . Biochemical and Biophysical Research Communications . 391 . 4 . 1762–8 . January 2010 . 20044979 . 10.1016/j.bbrc.2009.12.150 .
7. Goralski KB, McCarthy TC, Hanniman EA, Zabel BA, Butcher EC, Parlee SD, Muruganandan S, Sinal CJ . Chemerin, a novel adipokine that regulates adipogenesis and adipocyte metabolism . The Journal of Biological Chemistry . 282 . 38 . 28175–88 . September 2007 . 17635925 . 10.1074/jbc.M700793200 . free .
8. Takahashi M, Takahashi Y, Takahashi K, Zolotaryov FN, Hong KS, Kitazawa R, Iida K, Okimura Y, Kaji H, Kitazawa S, Kasuga M, Chihara K . Chemerin enhances insulin signaling and potentiates insulin-stimulated glucose uptake in 3T3-L1 adipocytes . FEBS Letters . 582 . 5 . 573–8 . March 2008 . 18242188 . 10.1016/j.febslet.2008.01.023 . 41312338 . free . 20.500.14094/D2003055 . free .
9. Cash JL, Hart R, Russ A, Dixon JP, Colledge WH, Doran J, Hendrick AG, Carlton MB, Greaves DR . Synthetic chemerin-derived peptides suppress inflammation through ChemR23 . The Journal of Experimental Medicine . 205 . 4 . 767–75 . April 2008 . 18391062 . 2292217 . 10.1084/jem.20071601 .
10. Cash JL, Christian AR, Greaves DR . Chemerin peptides promote phagocytosis in a ChemR23- and Syk-dependent manner . Journal of Immunology . 184 . 9 . 5315–24 . May 2010 . 20363975 . 10.4049/jimmunol.0903378 . 4237835 .
11. Ramos-Junior ES, Leite GA, Carmo-Silva CC, Taira TM, Neves KB, Colón DF, da Silva LA, Salvador SL, Tostes RC, Cunha FQ, Fukada SY . Adipokine Chemerin Bridges Metabolic Dyslipidemia and Alveolar Bone Loss in Mice . Journal of Bone and Mineral Research . December 2016 . 28029186 . 10.1002/jbmr.3072 . 32 . 5 . 974–984. free .
12. Kennedy AJ, Yang P, Read C, Kuc RE, Yang L, Taylor EJ, Taylor CW, Maguire JJ, Davenport AP . Chemerin Elicits Potent Constrictor Actions via Chemokine-Like Receptor 1 (CMKLR1), not G-Protein-Coupled Receptor 1 (GPR1), in Human and Rat Vasculature . Journal of the American Heart Association . 5 . 10 . e004421 . October 2016 . 27742615 . 5121526 . 10.1161/JAHA.116.004421 .
13. Darios ES, Winner BM, Charvat T, Krasinksi A, Punna S, Watts SW . The adipokine chemerin amplifies electrical field-stimulated contraction in the isolated rat superior mesenteric artery . American Journal of Physiology. Heart and Circulatory Physiology . 311 . 2 . H498-507 . August 2016 . 27371688 . 10.1152/ajpheart.00998.2015 . 5008655.
14. Web site: Chemerin receptor – IUPHAR/BPS Guide to Pharmacology . www.guidetopharmacology.org . 7 April 2017.
15. News: ChemoCentryx Identifies Novel Small Molecule ChemR23 Antagonist for the Treatment of Inflammatory Diseases . 2010-04-10 . ChemoCentryx . 2017-04-14 . https://web.archive.org/web/20110519141347/http://www.chemocentryx.com/news/2010/pr20100408.html . 2011-05-19 . dead .
16. News: ChemoCentryx, GSK discontinue ChemR23 antagonist. BioCentury. 7 February 2012.