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Complement peptide receptors C
Formerly known as: Anaphylatoxin receptors
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
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Complement peptide receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Complement peptide receptors [28]) are activated by the endogenous ~75 amino-acid anaphylatoxin polypeptides C3a (C3, P01024) and C5a (C5, P01031), generated upon stimulation of the complement cascade. C3a and C5a exert their functions through binding to their receptors (C3aR, C5aR1 and C5aR2), causing cell recruitment and triggering cellular degranulation that contributes to local inflammation.
Receptors
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C3a receptor
C
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C5a1 receptor
C
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C5a2 receptor
C
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Further reading
* Key recommended reading is highlighted with an asterisk
* Arbore G, Kemper C. (2016) A novel "complement-metabolism-inflammasome axis" as a key regulator of immune cell effector function. Eur J Immunol, 46 (7): 1563-73. [PMID:27184294]
Coulthard LG, Hawksworth OA, Conroy J, Lee JD, Woodruff TM. (2018) Complement C3a receptor modulates embryonic neural progenitor cell proliferation and cognitive performance. Mol Immunol, 101: 176-181. [PMID:30449309]
* Coulthard LG, Woodruff TM. (2015) Is the complement activation product C3a a proinflammatory molecule? Re-evaluating the evidence and the myth. J Immunol, 194 (8): 3542-8. [PMID:25848071]
Klos A, Wende E, Wareham KJ, Monk PN. (2013) International Union of Pharmacology. LXXXVII. Complement peptide C5a, C4a, and C3a receptors. Pharmacol Rev, 65 (1): 500-43. [PMID:23383423]
* Laumonnier Y, Karsten CM, Köhl J. (2017) Novel insights into the expression pattern of anaphylatoxin receptors in mice and men. Mol Immunol, 89: 44-58. [PMID:28600003]
Li R, Coulthard LG, Wu MC, Taylor SM, Woodruff TM. (2013) C5L2: a controversial receptor of complement anaphylatoxin, C5a. FASEB J, 27 (3): 855-64. [PMID:23239822]
* Li XX, Lee JD, Kemper C, Woodruff TM. (2019) The Complement Receptor C5aR2: A Powerful Modulator of Innate and Adaptive Immunity. J Immunol, 202 (12): 3339-3348. [PMID:31160390]
Manthey HD, Woodruff TM, Taylor SM, Monk PN. (2009) Complement component 5a (C5a). Int J Biochem Cell Biol, 41 (11): 2114-7. [PMID:19464229]
Monk PN, Scola AM, Madala P, Fairlie DP. (2007) Function, structure and therapeutic potential of complement C5a receptors. Br J Pharmacol, 152 (4): 429-48. [PMID:17603557]
* Pandey S, Maharana J, Li XX, Woodruff TM, Shukla AK. (2020) Emerging Insights into the Structure and Function of Complement C5a Receptors. Trends Biochem Sci, 45 (8): 693-705. [PMID:32402749]
* Reichhardt MP, Meri S. (2018) Intracellular complement activation-An alarm raising mechanism?. Semin Immunol, 38: 54-62. [PMID:29631809]
Sacks SH. (2010) Complement fragments C3a and C5a: the salt and pepper of the immune response. Eur J Immunol, 40 (3): 668-70. [PMID:20186746]
References
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2. Ames RS, Nuthulaganti P, Kumar C. (1996) In Xenopus oocytes the human C3a and C5a receptors elicit a promiscuous response to the anaphylatoxins. FEBS Lett, 395 (2-3): 157-9. [PMID:8898085]
3. Arbore G, West EE, Spolski R, Robertson AA, Klos A, Rheinheimer C, Dutow P, Woodruff TM, Yu ZX, O'Neill LA et al.. (2016) T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4⁺ T cells. Science, 352 (6292): aad1210. [PMID:27313051]
4. Bamberg CE, Mackay CR, Lee H, Zahra D, Jackson J, Lim YS, Whitfeld PL, Craig S, Corsini E, Lu B et al.. (2010) The C5a receptor (C5aR) C5L2 is a modulator of C5aR-mediated signal transduction. J Biol Chem, 285 (10): 7633-44. [PMID:20044484]
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9. Cain SA, Monk PN. (2002) The orphan receptor C5L2 has high affinity binding sites for complement fragments C5a and C5a des-Arg(74). J Biol Chem, 277 (9): 7165-9. [PMID:11773063]
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13. Coulthard LG, Woodruff TM. (2015) Is the complement activation product C3a a proinflammatory molecule? Re-evaluating the evidence and the myth. J Immunol, 194 (8): 3542-8. [PMID:25848071]
14. Croker DE, Halai R, Fairlie DP, Cooper MA. (2013) C5a, but not C5a-des Arg, induces upregulation of heteromer formation between complement C5a receptors C5aR and C5L2. Immunol Cell Biol, 91 (10): 625-33. [PMID:24060963]
15. Croker DE, Halai R, Kaeslin G, Wende E, Fehlhaber B, Klos A, Monk PN, Cooper MA. (2014) C5a2 can modulate ERK1/2 signaling in macrophages via heteromer formation with C5a1 and β-arrestin recruitment. Immunol Cell Biol, 92 (7): 631-9. [PMID:24777312]
16. Croker DE, Monk PN, Halai R, Kaeslin G, Schofield Z, Wu MC, Clark RJ, Blaskovich MA, Morikis D, Floudas CA et al.. (2016) Discovery of functionally selective C5aR2 ligands: novel modulators of C5a signalling. Immunol Cell Biol, 94 (8): 787-95. [PMID:27108698]
17. Dantas de Araujo A, Wu C, Wu KC, Reid RC, Durek T, Lim J, Fairlie DP. (2017) Europium-Labeled Synthetic C3a Protein as a Novel Fluorescent Probe for Human Complement C3a Receptor. Bioconjug Chem, 28 (6): 1669-1676. [PMID:28562031]
18. Gao H, Neff TA, Guo RF, Speyer CL, Sarma JV, Tomlins S, Man Y, Riedemann NC, Hoesel LM, Younkin E et al.. (2005) Evidence for a functional role of the second C5a receptor C5L2. FASEB J, 19 (8): 1003-5. [PMID:15784721]
19. Gavrilyuk V, Kalinin S, Hilbush BS, Middlecamp A, McGuire S, Pelligrino D, Weinberg G, Feinstein DL. (2005) Identification of complement 5a-like receptor (C5L2) from astrocytes: characterization of anti-inflammatory properties. J Neurochem, 92 (5): 1140-9. [PMID:15715664]
20. Hawksworth OA, Li XX, Coulthard LG, Wolvetang EJ, Woodruff TM. (2017) New concepts on the therapeutic control of complement anaphylatoxin receptors. Mol Immunol, 89: 36-43. [PMID:28576324]
21. Honczarenko M, Lu B, Nicholson-Weller A, Gerard NP, Silberstein LE, Gerard C. (2005) C5L2 receptor is not involved in C3a / C3a-desArg-mediated enhancement of bone marrow hematopoietic cell migration to CXCL12. Leukemia, 19 (9): 1682-3; author reply 1684-5. [PMID:15990859]
22. Huey R, Hugli TE. (1985) Characterization of a C5a receptor on human polymorphonuclear leukocytes (PMN). J Immunol, 135 (3): 2063-8. [PMID:4020139]
23. Jinsmaa Y, Takenaka Y, Yoshikawa M. (2001) Designing of an orally active complement C3a agonist peptide with anti-analgesic and anti-amnesic activity. Peptides, 22 (1): 25-32. [PMID:11179594]
24. Kalant D, Cain SA, Maslowska M, Sniderman AD, Cianflone K, Monk PN. (2003) The chemoattractant receptor-like protein C5L2 binds the C3a des-Arg77/acylation-stimulating protein. J Biol Chem, 278 (13): 11123-9. [PMID:12540846]
25. Kalant D, MacLaren R, Cui W, Samanta R, Monk PN, Laporte SA, Cianflone K. (2005) C5L2 is a functional receptor for acylation-stimulating protein. J Biol Chem, 280 (25): 23936-44. [PMID:15833747]
26. Kawai M, Quincy DA, Lane B, Mollison KW, Or YS, Luly JR, Carter GW. (1992) Structure-function studies in a series of carboxyl-terminal octapeptide analogues of anaphylatoxin C5a. J Med Chem, 35: 220-223. [PMID:1732540]
27. Kildsgaard J, Hollmann TJ, Matthews KW, Bian K, Murad F, Wetsel RA. (2000) Cutting edge: targeted disruption of the C3a receptor gene demonstrates a novel protective anti-inflammatory role for C3a in endotoxin-shock. J Immunol, 165 (10): 5406-9. [PMID:11067891]
28. Klos A, Wende E, Wareham KJ, Monk PN. (2013) International Union of Pharmacology. LXXXVII. Complement peptide C5a, C4a, and C3a receptors. Pharmacol Rev, 65 (1): 500-43. [PMID:23383423]
29. Konteatis ZD, Siciliano SJ, Van Riper G, Molineaux CJ, Pandya S, Fischer P, Rosen H, Mumford RA, Springer MS. (1994) Development of C5a receptor antagonists. Differential loss of functional responses. J Immunol, 153 (9): 4200-5. [PMID:7930622]
30. Li R, Coulthard LG, Wu MC, Taylor SM, Woodruff TM. (2013) C5L2: a controversial receptor of complement anaphylatoxin, C5a. FASEB J, 27 (3): 855-64. [PMID:23239822]
31. Li XX, Clark RJ, Woodruff TM. (2020) C5aR2 Activation Broadly Modulates the Signaling and Function of Primary Human Macrophages. J Immunol, 205 (4): 1102-1112. [PMID:32611725]
32. Li XX, Kumar V, Lee JD, Woodruff TM. (2020) The "C3aR Antagonist" SB290157 is a Partial C5aR2 Agonist. Front Pharmacol, 11: 591398. DOI: 10.3389/fphar.2020.591398 [PMID:33551801]
33. Li XX, Lee JD, Kemper C, Woodruff TM. (2019) The Complement Receptor C5aR2: A Powerful Modulator of Innate and Adaptive Immunity. J Immunol, 202 (12): 3339-3348. [PMID:31160390]
34. Li XX, Lee JD, Massey NL, Guan C, Robertson AAB, Clark RJ, Woodruff TM. (2020) Pharmacological characterisation of small molecule C5aR1 inhibitors in human cells reveals biased activities for signalling and function. Biochem Pharmacol, 180: 114156. [PMID:32682759]
35. March DR, Proctor LM, Stoermer MJ, Sbaglia R, Abbenante G, Reid RC, Woodruff TM, Wadi K, Paczkowski N, Tyndall JD et al.. (2004) Potent cyclic antagonists of the complement C5a receptor on human polymorphonuclear leukocytes. Relationships between structures and activity. Mol Pharmacol, 65 (4): 868-79. [PMID:15044616]
36. Mathieu MC, Sawyer N, Greig GM, Hamel M, Kargman S, Ducharme Y, Lau CK, Friesen RW, O'Neill GP, Gervais FG et al.. (2005) The C3a receptor antagonist SB 290157 has agonist activity. Immunol Lett, 100 (2): 139-45. [PMID:16154494]
37. Miyabe Y, Miyabe C, Mani V, Mempel TR, Luster AD. (2019) Atypical complement receptor C5aR2 transports C5a to initiate neutrophil adhesion and inflammation. Sci Immunol, 4 (35). DOI: 10.1126/sciimmunol.aav5951 [PMID:31076525]
38. Monk PN, Scola AM, Madala P, Fairlie DP. (2007) Function, structure and therapeutic potential of complement C5a receptors. Br J Pharmacol, 152 (4): 429-48. [PMID:17603557]
39. Moriconi A, Cunha TM, Souza GR, Lopes AH, Cunha FQ, Carneiro VL, Pinto LG, Brandolini L, Aramini A, Bizzarri C et al.. (2014) Targeting the minor pocket of C5aR for the rational design of an oral allosteric inhibitor for inflammatory and neuropathic pain relief. Proc Natl Acad Sci USA, 111 (47): 16937-42. [PMID:25385614]
40. Nabizadeh JA, Manthey HD, Steyn FJ, Chen W, Widiapradja A, Md Akhir FN, Boyle GM, Taylor SM, Woodruff TM, Rolfe BE. (2016) The Complement C3a Receptor Contributes to Melanoma Tumorigenesis by Inhibiting Neutrophil and CD4+ T Cell Responses. J Immunol, 196 (11): 4783-92. [PMID:27183625]
41. Okinaga S, Slattery D, Humbles A, Zsengeller Z, Morteau O, Kinrade MB, Brodbeck RM, Krause JE, Choe HR, Gerard NP et al.. (2003) C5L2, a nonsignaling C5A binding protein. Biochemistry, 42 (31): 9406-15. [PMID:12899627]
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NC-IUPHAR subcommittee and family contributors
Subcommittee members:
Trent M. Woodruff (Chairperson) |
Other contributors:
Antonia Cianciulli
Liam Coulthard
Owen Hawksworth
John D. Lee
Xaria X. Li
Vincenzo Mitolo
Maria A. Panaro |
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie A, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2019) The Concise Guide to PHARMACOLOGY 2019/20: G protein-coupled receptors. Br J Pharmacol. 176 Issue S1: S21-S141.
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SB290157 has also been reported to have agonist properties at the C3a receptor [32,36]. The chemoattractant receptor C5a2 (also known as GPR77, C5L2) binds C5a and has putative roles in either opposing or promoting inflammatory responses [9,18-19,33,43]. Binding to this site may be displaced with the rank order C5a des-Arg (C5)> C5a (C5, P01031) [9,41] while there is controversy over the ability of C3a (C3, P01024) and C3a des Arg (C3, P01024) to compete [21,24-25,41]. C5a2 appears to lack G protein signalling and has been termed a decoy receptor [47]. However, C5a2 does recruit β-arrestin 2 after ligand binding, which might provide a signaling pathway for this receptor [4,53], and forms heteromers with C5a1. C5a, but not C5a-des Arg, induces upregulation of heteromer formation between complement C5a receptors C5a1 and C5a2 [14]. There are also reports of pro-inflammatory activity of C5a2, mediated by HMGB1, likely through AKT and MAPK signalling pathways (reviewed in [30,60]). In T cells it has been shown that C5a1 and C5a2 act in opposition to each other and that altering the equilibrium between the two receptors, by differential expression or production of C5a-des Arg (which favours C5a2), can affect the final cellular response [3]. Recently in human macrophages, C5a2 was observed to modulate multiple complement and chemokine receptor-mediated signalling and pattern recognition-induced cytokine responses, independent of C5a1 [31]. In addition, C5a2 is reported to act as a C5a transporter on endothelial cells, and is required for the transport of C5a into the vessel lumen and the subsequent neutrophil arrest in arthritis [37].