Complement peptide receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Complement peptide receptors [22]) are activated by the endogenous ~75 amino-acid anaphylatoxin polypeptides C3a (C3, P01024) and C5a (C5, P01031), generated upon stimulation of the complement cascade.

SB290157 has also been reported to have agonist properties at the C3a receptor [25]. The putative chemoattractant receptor termed C5a₂ (also known as GPR77, C5L2) binds [¹²⁵I]C5a with no clear signalling function, but has a putative role opposing inflammatory responses [9,14-15]. Binding to this site may be displaced with the rank order C5a des-Arg (C5)> C5a (C5, P01031) [9,27] while there is controversy over the ability of C3a (C3, P01024) and C3a des Arg (C3, P01024) to compete [17,19-20,27]. C5a₂ appears to lack G protein signalling and has been termed a decoy receptor [30]. However, C5a₂ does recruit arrestin after ligand binding, which might provide a signaling pathway for this receptor [5,32], and forms heteromers with C5a₁. C5a, but not C5a-des Arg, induces upregulation of heteromer formation between complement C5a receptors C5a₁ and C5a₂ [11]. There are also reports of pro-inflammatory activity of C5a₂, mediated by HMGB1, but the signaling pathway that underlies this is currently unclear (reviewed in [24]). More recently, work in T cells has 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 [4].

* 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, 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]

Hajishengallis G. (2010) Complement and periodontitis. Biochem. Pharmacol., 80 (12): 1992-2001. [PMID:20599785]

* 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]

* 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]

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]

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]

1. Ames RS, Lee D, Foley JJ, Jurewicz AJ, Tornetta MA, Bautsch W, Settmacher B, Klos A, Erhard KF, Cousins RD et al.. (2001) Identification of a selective nonpeptide antagonist of the anaphylatoxin C3a receptor that demonstrates antiinflammatory activity in animal models. J. Immunol., 166 (10): 6341-8. [PMID:11342658]

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. Ames RS, Tornetta MA, Foley JJ, Hugli TE, Sarau HM. (1997) Evidence that the receptor for C4a is distinct from the C3a receptor. Immunopharmacology, 38 (1-2): 87-92. [PMID:9476119]

4. 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]

5. 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]

6. Bekker P, Dairaghi D, Seitz L, Leleti M, Wang Y, Ertl L, Baumgart T, Shugarts S, Lohr L, Dang T et al.. (2016) Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study. PLoS ONE, 11 (10): e0164646. [PMID:27768695]

7. Brodbeck RM, Cortright DN, Kieltyka AP, Yu J, Baltazar CO, Buck ME, Meade R, Maynard GD, Thurkauf A, Chien DS et al.. (2008) Identification and characterization of NDT 9513727 [N,N-bis(1,3-benzodioxol-5-ylmethyl)-1-butyl-2,4-diphenyl-1H-imidazole-5-methanamine], a novel, orally bioavailable C5a receptor inverse agonist. J. Pharmacol. Exp. Ther., 327 (3): 898-909. [PMID:18753409]

8. Buhl AM, Eisfelder BJ, Worthen GS, Johnson GL, Russell M. (1993) Selective coupling of the human anaphylatoxin C5a receptor and alpha 16 in human kidney 293 cells. FEBS Lett., 323 (1-2): 132-4. [PMID:8388335]

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]

10. Chao TH, Ember JA, Wang M, Bayon Y, Hugli TE, Ye RD. (1999) Role of the second extracellular loop of human C3a receptor in agonist binding and receptor function. J. Biol. Chem., 274 (14): 9721-8. [PMID:10092660]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. Halai R, Bellows-Peterson ML, Branchett W, Smadbeck J, Kieslich CA, Croker DE, Cooper MA, Morikis D, Woodruff TM, Floudas CA et al.. (2014) Derivation of ligands for the complement C3a receptor from the C-terminus of C5a. Eur. J. Pharmacol., 745: 176-81. [PMID:25446428]

17. 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]

18. Huey R, Hugli TE. (1985) Characterization of a C5a receptor on human polymorphonuclear leukocytes (PMN). J. Immunol., 135 (3): 2063-8. [PMID:4020139]

19. 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]

20. 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]

21. 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]

22. 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]

23. 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: 4200-4205. [PMID:7930622]

24. 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]

25. 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]

26. 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. U.S.A., 111 (47): 16937-42. [PMID:25385614]

27. 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]

28. Reid RC, Yau MK, Singh R, Hamidon JK, Lim J, Stoermer MJ, Fairlie DP. (2014) Potent heterocyclic ligands for human complement c3a receptor. J. Med. Chem., 57 (20): 8459-70. [PMID:25259874]

29. Reid RC, Yau MK, Singh R, Hamidon JK, Reed AN, Chu P, Suen JY, Stoermer MJ, Blakeney JS, Lim J et al.. (2013) Downsizing a human inflammatory protein to a small molecule with equal potency and functionality. Nat Commun, 4: 2802. [PMID:24257095]

30. Scola AM, Johswich KO, Morgan BP, Klos A, Monk PN. (2009) The human complement fragment receptor, C5L2, is a recycling decoy receptor. Mol. Immunol., 46 (6): 1149-62. [PMID:19100624]

31. Sumichika H, Sakata K, Sato N, Takeshita S, Ishibuchi S, Nakamura M, Kamahori T, Ehara S, Itoh K, Ohtsuka T et al.. (2002) Identification of a potent and orally active non-peptide C5a receptor antagonist. J. Biol. Chem., 277 (51): 49403-7. [PMID:12384495]

32. Van Lith LH, Oosterom J, Van Elsas A, Zaman GJ. (2009) C5a-stimulated recruitment of beta-arrestin2 to the nonsignaling 7-transmembrane decoy receptor C5L2. J Biomol Screen, 14 (9): 1067-75. [PMID:19641221]

33. Wong AK, Finch AM, Pierens GK, Craik DJ, Taylor SM, Fairlie DP. (1998) Small molecular probes for G-protein-coupled C5a receptors: conformationally constrained antagonists derived from the C terminus of the human plasma protein C5a. J. Med. Chem., 41 (18): 3417-25. [PMID:9719594]

34. Yamamoto T. (2000) Molecular mechanism of monocyte predominant infiltration in chronic inflammation: mediation by a novel monocyte chemotactic factor, S19 ribosomal protein dimer. Pathol. Int., 50 (11): 863-71. [PMID:11107061]

Subcommittee members: Trent Woodruff (Chairperson) School of Biomedical Sciences The University of Queensland BNE, QUEENSLAND 4072 Australia Peter Monk Department of Infection and Immunity Sheffield University Medical School Beech Hill Road Sheffield S10 2RX, UK

Other contributors: Liam Coulthard School of Biomedical Sciences The University of Queensland BNE, QUEENSLAND 4072 Owen Hawksworth School of Biomedical Sciences The University of Queensland BNE, QUEENSLAND 4072 Australia Vincenzo Mitolo Department of Pharmaco-Biology University of Bari Italy Maria A. Panaro Department of Pharmaco-Biology University of Bari Italy