C5a receptor explained

The C5a receptor also known as complement component 5a receptor 1 (C5AR1) or CD88 (Cluster of Differentiation 88) is a G protein-coupled receptor for C5a. It functions as a complement receptor.^[1] C5a receptor 1 modulates inflammatory responses, obesity, development and cancers.^{[2] [3] [4]} From a signaling transduction perspective, C5a receptor 1 activation is implicated in β-arrestin2 recruitment via Rab5a,^[5] coupling of Gαi proteins,^[6] ERK1/2 phosphorylation, ^[7] calcium mobilization and Rho activation^[8] leading to downstream functions, such as secretion of cytokines, chemotaxis, and phagocytosis.

Cells

The C5a receptor 1 is expressed on:^[9]

• Granulocytes
• Macrophages
• Monocytes
• Dendritic cells
• Hepatoma-derived cell line HepG2
• Astrocytes
• Microglia

Agonist and antagonists

Potent and selective agonist and antagonists for C5a receptor 1 have been developed.^{[10] [11] [12] [13] [14] [15]}

See also

• Complement component 5a for binding mechanism

Further reading

• Sengeløv H . Complement receptors in neutrophils . Critical Reviews in Immunology . 15 . 2 . 107–131 . 1996 . 8573284 . 10.1615/critrevimmunol.v15.i2.10 .
• Beil WJ, Schulz M, Wefelmeyer U . Mast cell granule composition and tissue location--a close correlation . Histology and Histopathology . 15 . 3 . 937–946 . July 2000 . 10963136 .
• Yamamoto T . Roles of the ribosomal protein S19 dimer and the C5a receptor in pathophysiological functions of phagocytic leukocytes . Pathology International . 57 . 1 . 1–11 . January 2007 . 17199736 . 10.1111/j.1440-1827.2007.02049.x . 22946804 .
• Bao L, Gerard NP, Eddy RL, Shows TB, Gerard C . Mapping of genes for the human C5a receptor (C5AR), human FMLP receptor (FPR), and two FMLP receptor homologue orphan receptors (FPRH1, FPRH2) to chromosome 19 . Genomics . 13 . 2 . 437–440 . June 1992 . 1612600 . 10.1016/0888-7543(92)90265-T .
• Gerard NP, Gerard C . The chemotactic receptor for human C5a anaphylatoxin . Nature . 349 . 6310 . 614–617 . February 1991 . 1847994 . 10.1038/349614a0 . 4338594 . 1991Natur.349..614G .
• Boulay F, Mery L, Tardif M, Brouchon L, Vignais P . Expression cloning of a receptor for C5a anaphylatoxin on differentiated HL-60 cells . Biochemistry . 30 . 12 . 2993–2999 . March 1991 . 2007135 . 10.1021/bi00226a002 .
• Wahl SM, Allen JB, Gartner S, Orenstein JM, Popovic M, Chenoweth DE, Arthur LO, Farrar WL, Wahl LM . HIV-1 and its envelope glycoprotein down-regulate chemotactic ligand receptors and chemotactic function of peripheral blood monocytes . Journal of Immunology . 142 . 10 . 3553–3559 . May 1989 . 2541200 . 10.4049/jimmunol.142.10.3553 . 44347771 . free .
• Foreman KE, Vaporciyan AA, Bonish BK, Jones ML, Johnson KJ, Glovsky MM, Eddy SM, Ward PA . C5a-induced expression of P-selectin in endothelial cells . The Journal of Clinical Investigation . 94 . 3 . 1147–1155 . September 1994 . 7521884 . 295185 . 10.1172/JCI117430 .
• Giannini E, Brouchon L, Boulay F . Identification of the major phosphorylation sites in human C5a anaphylatoxin receptor in vivo . The Journal of Biological Chemistry . 270 . 32 . 19166–19172 . August 1995 . 7642584 . 10.1074/jbc.270.32.19166 . free .
• Buhl AM, Osawa S, Johnson GL . Mitogen-activated protein kinase activation requires two signal inputs from the human anaphylatoxin C5a receptor . The Journal of Biological Chemistry . 270 . 34 . 19828–19832 . August 1995 . 7649993 . 10.1074/jbc.270.34.19828 . free .
• Wennogle LP, Conder L, Winter C, Braunwalder A, Vlattas S, Kramer R, Cioffi C, Hu SI . Stabilization of C5a receptor--G-protein interactions through ligand binding . Journal of Cellular Biochemistry . 55 . 3 . 380–388 . July 1994 . 7962171 . 10.1002/jcb.240550316 . 36216040 .
• Gerard NP, Bao L, Xiao-Ping H, Eddy RL, Shows TB, Gerard C . Human chemotaxis receptor genes cluster at 19q13.3-13.4. Characterization of the human C5a receptor gene . Biochemistry . 32 . 5 . 1243–1250 . February 1993 . 8383526 . 10.1021/bi00056a007 .
• Ames RS, Li Y, Sarau HM, Nuthulaganti P, Foley JJ, Ellis C, Zeng Z, Su K, Jurewicz AJ, Hertzberg RP, Bergsma DJ, Kumar C . Molecular cloning and characterization of the human anaphylatoxin C3a receptor . The Journal of Biological Chemistry . 271 . 34 . 20231–20234 . August 1996 . 8702752 . 10.1074/jbc.271.34.20231 . free .
• Werfel T, Zwirner J, Oppermann M, Sieber A, Begemann G, Drommer W, Kapp A, Götze O . CD88 antibodies specifically bind to C5aR on dermal CD117+ and CD14+ cells and react with a desmosomal antigen in human skin . Journal of Immunology . 157 . 4 . 1729–1735 . August 1996 . 8759762 . 10.4049/jimmunol.157.4.1729 . 20748991 . free .
• Höpken UE, Lu B, Gerard NP, Gerard C . The C5a chemoattractant receptor mediates mucosal defence to infection . Nature . 383 . 6595 . 86–89 . September 1996 . 8779720 . 10.1038/383086a0 . 4346934 . 1996Natur.383...86H .
• Chen Z, Zhang X, Gonnella NC, Pellas TC, Boyar WC, Ni F . Residues 21-30 within the extracellular N-terminal region of the C5a receptor represent a binding domain for the C5a anaphylatoxin . The Journal of Biological Chemistry . 273 . 17 . 10411–10419 . April 1998 . 9553099 . 10.1074/jbc.273.17.10411 . free .
• Floreani AA, Heires AJ, Welniak LA, Miller-Lindholm A, Clark-Pierce L, Rennard SI, Morgan EL, Sanderson SD . Expression of receptors for C5a anaphylatoxin (CD88) on human bronchial epithelial cells: enhancement of C5a-mediated release of IL-8 upon exposure to cigarette smoke . Journal of Immunology . 160 . 10 . 5073–5081 . May 1998 . 9590258 . 10.4049/jimmunol.160.10.5073 . free .
• Ottonello L, Corcione A, Tortolina G, Airoldi I, Albesiano E, Favre A, D'Agostino R, Malavasi F, Pistoia V, Dallegri F . rC5a directs the in vitro migration of human memory and naive tonsillar B lymphocytes: implications for B cell trafficking in secondary lymphoid tissues . Journal of Immunology . 162 . 11 . 6510–6517 . June 1999 . 10352266 . 10.4049/jimmunol.162.11.6510 . free .
• Kohleisen B, Shumay E, Sutter G, Foerster R, Brack-Werner R, Nuesse M, Erfle V . Stable expression of HIV-1 Nef induces changes in growth properties and activation state of human astrocytes . AIDS . 13 . 17 . 2331–2341 . December 1999 . 10597774 . 10.1097/00002030-199912030-00004 .
• Monk PN, Scola AM, Madala P, Fairlie DP . Function, structure and therapeutic potential of complement C5a receptors . British Journal of Pharmacology . 152 . 4 . 429–448 . October 2007 . 17603557 . 2050825 . 10.1038/sj.bjp.0707332 .

External links

• Web site: Anaphylatoxin Receptors: C5a . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2007-10-25 . 2014-04-07 . https://web.archive.org/web/20140407074942/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2972 . dead .

Notes and References

1. Gerard C, Gerard NP . C5A anaphylatoxin and its seven transmembrane-segment receptor . Annual Review of Immunology . 12 . 775–808 . 1994 . 8011297 . 10.1146/annurev.iy.12.040194.004015 .
2. Brennan FH, Gordon R, Lao HW, Biggins PJ, Taylor SM, Franklin RJ, Woodruff TM, Ruitenberg MJ . The Complement Receptor C5aR Controls Acute Inflammation and Astrogliosis following Spinal Cord Injury . The Journal of Neuroscience . 35 . 16 . 6517–6531 . April 2015 . 25904802 . 6605214 . 10.1523/JNEUROSCI.5218-14.2015 .
3. Lim J, Iyer A, Suen JY, Seow V, Reid RC, Brown L, Fairlie DP . C5aR and C3aR antagonists each inhibit diet-induced obesity, metabolic dysfunction, and adipocyte and macrophage signaling . FASEB Journal . 27 . 2 . 822–831 . February 2013 . 23118029 . 10.1096/fj.12-220582 . free . 25562647 .
4. Markiewski MM, DeAngelis RA, Benencia F, Ricklin-Lichtsteiner SK, Koutoulaki A, Gerard C, Coukos G, Lambris JD . Modulation of the antitumor immune response by complement . Nature Immunology . 9 . 11 . 1225–1235 . November 2008 . 18820683 . 2678913 . 10.1038/ni.1655 .
5. Wu KC, Condon ND, Hill TA, Reid RC, Fairlie D, Lim J . Ras related protein Rab5a regulates complement C5a receptor trafficking, chemotaxis and chemokine secretion in human macrophages . Journal of Innate Immunity . 15 . 1 . 468–484 . March 2023 . 36882040 . 10.1159/000530012 . 10105068 .
6. Feng Y, Zhao C, Deng Y, Wang H, Ma L, Liu S, Tian X, Wang B, Bin Y, Chen P, Yan W, Fu P, Shao Z . Mechanism of activation and biased signaling in complement receptor C5aR1 . Cell Research . 33 . 4 . 312–324 . April 2023 . 36806352 . 10.1038/s41422-023-00779-2 . 9937529 .
7. Li XX, Lee JD, Massey NL, Guan C, Robertson AA, Clark RJ, Woodruff TM . Pharmacological characterisation of small molecule C5aR1 inhibitors in human cells reveals biased activities for signalling and function . Biochemical Pharmacology . 180 . 114156 . October 2020 . 32682759 . 10.1016/j.bcp.2020.114156 . 220653568 .
8. Wang X, Iyer A, Lyons AB, Körner H, Wei W . Emerging Roles for G-protein Coupled Receptors in Development and Activation of Macrophages . Frontiers in Immunology . 10 . 2031 . 2019 . 31507616 . 6718513 . 10.3389/fimmu.2019.02031 . free .
9. Klos A, Wende E, Wareham KJ, Monk PN . International Union of Basic and Clinical Pharmacology. [corrected]. LXXXVII. Complement peptide C5a, C4a, and C3a receptors . Pharmacological Reviews . 65 . 1 . 500–543 . January 2013 . 23383423 . 10.1124/pr.111.005223 . free .
10. Gorman DM, Li XX, Lee JD, Fung JN, Cui CS, Lee HS, Rolfe BE, Woodruff TM, Clark RJ . Development of Potent and Selective Agonists for Complement C5a Receptor 1 with In Vivo Activity . Journal of Medicinal Chemistry . 64 . 22 . 16598–16608 . November 2021 . 34762432 . 10.1021/acs.jmedchem.1c01174 . 244040645 .
11. Wong AK, Finch AM, Pierens GK, Craik DJ, Taylor SM, Fairlie DP . Small molecular probes for G-protein-coupled C5a receptors: conformationally constrained antagonists derived from the C terminus of the human plasma protein C5a . Journal of Medicinal Chemistry . 41 . 18 . 3417–3425 . August 1998 . 9719594 . 10.1021/jm9800651 .
12. Gong Y, Barbay JK, Buntinx M, Li J, Wauwe JV, Claes C, Lommen GV, Hornby PJ, He W . Design and optimization of aniline-substituted tetrahydroquinoline C5a receptor antagonists . Bioorganic & Medicinal Chemistry Letters . 18 . 14 . 3852–3855 . July 2008 . 18595693 . 10.1016/j.bmcl.2008.06.059 .
13. Sumichika H, Sakata K, Sato N, Takeshita S, Ishibuchi S, Nakamura M, Kamahori T, Ehara S, Itoh K, Ohtsuka T, Ohbora T, Mishina T, Komatsu H, Naka Y . Identification of a potent and orally active non-peptide C5a receptor antagonist . The Journal of Biological Chemistry . 277 . 51 . 49403–49407 . December 2002 . 12384495 . 10.1074/jbc.M209672200 . free .
14. Seow V, Lim J, Cotterell AJ, Yau MK, Xu W, Lohman RJ, Kok WM, Stoermer MJ, Sweet MJ, Reid RC, Suen JY, Fairlie DP . Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of complement C5a antagonists . Scientific Reports . 6 . 1 . 24575 . April 2016 . 27094554 . 4837355 . 10.1038/srep24575 . 2016NatSR...624575S .
15. Ulrich JT, Cieplak W, Paczkowski NJ, Taylor SM, Sanderson SD . Induction of an antigen-specific CTL response by a conformationally biased agonist of human C5a anaphylatoxin as a molecular adjuvant . Journal of Immunology . 164 . 10 . 5492–5498 . May 2000 . 10799917 . 10.4049/jimmunol.164.10.5492 . 38942679 . free .