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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 [35]) 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 (C3a receptor, C5a receptor 1 and C5a receptor 2), 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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39. 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]
40. Li XX, Kumar V, Clark RJ, Lee JD, Woodruff TM. (2020) The "C3aR Antagonist" SB290157 is a Partial C5aR2 Agonist. Front Pharmacol, 11: 591398. [PMID:33551801]
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42. 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]
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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 SP, Christopoulos A, Davenport AP, Kelly E, Mathie A, Peters JA, Veale EL et al. (2021) THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors. Br J Pharmacol. 176 Suppl 1:S27-S156.
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SB290157 has also been reported to have agonist properties at the C3a receptor [40,44]. The chemoattractant receptor C5a2 (also known as GPR77, C5L2) binds C5a and has putative roles in either opposing or promoting inflammatory responses [11,21-22,41,55]. Binding to this site may be displaced with the rank order C5a des-Arg (C5) > C5a (C5, P01031) [11,51] while there is controversy over the ability of C3a (C3, P01024) and C3a des Arg (C3, P01024) to compete [28,31-32,51]. C5a2 appears to lack G protein signalling and has been termed a decoy receptor [59]. However, C5a2 does recruit β-arrestin 2 after ligand binding, which might provide a signalling pathway for this receptor [5,65], and forms heteromers with C5a1. A recent study has identified p90RSK (90 kDa ribosomal s6 kinase) phosphorylation as a potential signalling pathway for C5a2 [53]. C5a, but not C5a-des Arg, induces upregulation of heterodimer formation between complement C5a receptors C5a1 and C5a2 [16]. There are also reports of pro-inflammatory activity of C5a2, mediated by HMGB1, likely through AKT and MAPK signalling pathways (reviewed in [38,71]). 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 [4]. In human macrophages, C5a2 was observed to modulate multiple complement and chemokine receptor-mediated signalling and pattern recognition-induced cytokine responses, independent of C5a1 [39]. 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 [45].