F
IPR001644

C3a anaphylatoxin chemotactic receptor

InterPro entry
Short nameAnaphtx_C3AR1
family relationships

Description

The activation of the complement cascade produces a number of small fragments that are bioactive: potent chemoattractants and secretagogues that act on immune and non-immune cells
[15]
. Similar peptides can also be released by the actions of non-complement proteases, for instance during clotting
[16]
. Initially these were termed anaphylatoxins because of their effect on mast cell histamine release, but were reclassified as complement component peptides. They include C3a and C5a, which are involved immune response
[17]
, neural development and organ regeneration
[18, 19]
. A third peptide, C4a, has a similar structure, but it is inactive in humans
[21]
. Since the primary function of complement component peptides is in inflammation, they are important targets for the development of anti-inflammatory therapies
[19]
.

The anaphylatoxin chemotactic receptors (also known as complement peptide receptors) are a group of rhodopsin-like G-protein coupled receptors (GPCRs)
[24, 3, 4, 1]
. There are three subtypes: C3a anaphylatoxin chemotactic receptor (C3AR1)
[10]
, C5a anaphylatoxin chemotactic receptor (C5AR1)
[2]
and C5a anaphylatoxin chemotactic receptor C5L2 (C5AR2)
[6]
. Both C3AR1 and C5AR1 receptors are classical GPCRs. However, C5AR2 appears to be permanently uncoupled from G proteins but can associate with beta-arrestin
[7]
. Nevertheless, it has been shown that activation of both C5AR1 and C5AR2 is required for a full pro-inflammatory response, particularly in mice
[5]
. Several receptor antagonists have been reported
[15, 8, 9, 14]
, although none, so far, have been show to be effective in humans.

This entry represents C3AR1, also known as complement component 3a receptor 1 and C3aR
[10]
. It appears to be widely expressed in different lymphoid tissues, providing evidence for a central role in inflammatory processes
[26]
. This receptor stimulates chemotaxis
[11]
, granule enzyme release
[12, 13]
and increases phosphorylated-ERK1/2 production
[20]
. C3AR1 may provide a theraputic avenue for the treatment of asthma
[22]
, retinal degeneration
[23]
, and rheumatoid arthritis
[25]
.

References

1.cDNA cloning of a novel G protein-coupled receptor with a large extracellular loop structure. Roglic A, Prossnitz ER, Cavanagh SL, Pan Z, Zou A, Ye RD. Biochim. Biophys. Acta 1305, 39-43, (1996). View articlePMID: 8605247

2.The chemotactic receptor for human C5a anaphylatoxin. Gerard NP, Gerard C. Nature 349, 614-7, (1991). View articlePMID: 1847994

3.Identification of four novel human G protein-coupled receptors expressed in the brain. Lee DK, George SR, Cheng R, Nguyen T, Liu Y, Brown M, Lynch KR, O'Dowd BF. Brain Res. Mol. Brain Res. 86, 13-22, (2001). View articlePMID: 11165367

4.C5A anaphylatoxin and its seven transmembrane-segment receptor. Gerard C, Gerard NP. Annu. Rev. Immunol. 12, 775-808, (1994). View articlePMID: 8011297

5.C5L2 is critical for the biological activities of the anaphylatoxins C5a and C3a. Chen NJ, Mirtsos C, Suh D, Lu YC, Lin WJ, McKerlie C, Lee T, Baribault H, Tian H, Yeh WC. Nature 446, 203-7, (2007). View articlePMID: 17322907

6.Phylogenetic analysis of 277 human G-protein-coupled receptors as a tool for the prediction of orphan receptor ligands. Joost P, Methner A. Genome Biol. 3, RESEARCH0063, (2002). PMID: 12429062

7.C5L2 is a functional receptor for acylation-stimulating protein. Kalant D, MacLaren R, Cui W, Samanta R, Monk PN, Laporte SA, Cianflone K. J. Biol. Chem. 280, 23936-44, (2005). View articlePMID: 15833747

8.Identification of a selective nonpeptide antagonist of the anaphylatoxin C3a receptor that demonstrates antiinflammatory activity in animal models. Ames RS, Lee D, Foley JJ, Jurewicz AJ, Tornetta MA, Bautsch W, Settmacher B, Klos A, Erhard KF, Cousins RD, Sulpizio AC, Hieble JP, McCafferty G, Ward KW, Adams JL, Bondinell WE, Underwood DC, Osborn RR, Badger AM, Sarau HM. J. Immunol. 166, 6341-8, (2001). PMID: 11342658

9.The C3a receptor antagonist SB 290157 has agonist activity. Mathieu MC, Sawyer N, Greig GM, Hamel M, Kargman S, Ducharme Y, Lau CK, Friesen RW, O'Neill GP, Gervais FG, Therien AG. Immunol. Lett. 100, 139-45, (2005). View articlePMID: 16154494

10.Molecular cloning and characterization of the human anaphylatoxin C3a receptor. Ames RS, Li Y, Sarau HM, Nuthulaganti P, Foley JJ, Ellis C, Zeng Z, Su K, Jurewicz AJ, Hertzberg RP, Bergsma DJ, Kumar C. J. Biol. Chem. 271, 20231-4, (1996). View articlePMID: 8702752

11.C3a and C5a stimulate chemotaxis of human mast cells. Hartmann K, Henz BM, Kruger-Krasagakes S, Kohl J, Burger R, Guhl S, Haase I, Lippert U, Zuberbier T. Blood 89, 2863-70, (1997). PMID: 9108406

12.De novo peptide design with C3a receptor agonist and antagonist activities: theoretical predictions and experimental validation. Bellows-Peterson ML, Fung HK, Floudas CA, Kieslich CA, Zhang L, Morikis D, Wareham KJ, Monk PN, Hawksworth OA, Woodruff TM. J. Med. Chem. 55, 4159-68, (2012). View articlePMID: 22500977

13.Degranulation from human eosinophils stimulated with C3a and C5a. Takafuji S, Tadokoro K, Ito K, Dahinden CA. Int. Arch. Allergy Immunol. 104 Suppl 1, 27-9, (1994). PMID: 8156000

14.C5a mutants are potent antagonists of the C5a receptor (CD88) and of C5L2: position 69 is the locus that determines agonism or antagonism. Otto M, Hawlisch H, Monk PN, Muller M, Klos A, Karp CL, Kohl J. J. Biol. Chem. 279, 142-51, (2004). View articlePMID: 14570896

15.Function, structure and therapeutic potential of complement C5a receptors. Monk PN, Scola AM, Madala P, Fairlie DP. Br. J. Pharmacol. 152, 429-48, (2007). View articlePMID: 17603557

16.Interaction between the coagulation and complement system. Amara U, Rittirsch D, Flierl M, Bruckner U, Klos A, Gebhard F, Lambris JD, Huber-Lang M. Adv. Exp. Med. Biol. 632, 71-9, (2008). PMID: 19025115

17.The role of anaphylatoxins C3a and C5a in regulating innate and adaptive immune responses. Peng Q, Li K, Sacks SH, Zhou W. Inflamm Allergy Drug Targets 8, 236-46, (2009). View articlePMID: 19601884

18.Complement fragment C3a controls mutual cell attraction during collective cell migration. Carmona-Fontaine C, Theveneau E, Tzekou A, Tada M, Woods M, Page KM, Parsons M, Lambris JD, Mayor R. Dev. Cell 21, 1026-37, (2011). View articlePMID: 22118769

19.The role of the anaphylatoxins in health and disease. Klos A, Tenner AJ, Johswich KO, Ager RR, Reis ES, Kohl J. Mol. Immunol. 46, 2753-66, (2009). View articlePMID: 19477527

20.C3a and C5a are chemotactic factors for human mesenchymal stem cells, which cause prolonged ERK1/2 phosphorylation. Schraufstatter IU, Discipio RG, Zhao M, Khaldoyanidi SK. J. Immunol. 182, 3827-36, (2009). View articlePMID: 19265162

21.Human anaphylatoxin C4a is a potent agonist of the guinea pig but not the human C3a receptor. Lienenklaus S, Ames RS, Tornetta MA, Sarau HM, Foley JJ, Crass T, Sohns B, Raffetseder U, Grove M, Holzer A, Klos A, Kohl J, Bautsch W. J. Immunol. 161, 2089-93, (1998). PMID: 9725198

22.Th17 cytokines are critical for respiratory syncytial virus-associated airway hyperreponsiveness through regulation by complement C3a and tachykinins. Bera MM, Lu B, Martin TR, Cui S, Rhein LM, Gerard C, Gerard NP. J. Immunol. 187, 4245-55, (2011). View articlePMID: 21918196

23.A novel role of complement in retinal degeneration. Yu M, Zou W, Peachey NS, McIntyre TM, Liu J. Invest. Ophthalmol. Vis. Sci. 53, 7684-92, (2012). View articlePMID: 23074214

24.Characterization of receptors to the anaphylatoxins on isolated cells. Fukuoka Y, Nielsen LP, Hugli TE. Dermatologica 179 Suppl 1, 35-40, (1989). PMID: 2528484

25.Role of C3a receptors, C5a receptors, and complement protein C6 deficiency in collagen antibody-induced arthritis in mice. Banda NK, Hyatt S, Antonioli AH, White JT, Glogowska M, Takahashi K, Merkel TJ, Stahl GL, Mueller-Ortiz S, Wetsel R, Arend WP, Holers VM. J. Immunol. 188, 1469-78, (2012). View articlePMID: 22205026

26.Expression cloning of the human C3a anaphylatoxin receptor (C3aR) from differentiated U-937 cells. Crass T, Raffetseder U, Martin U, Grove M, Klos A, Kohl J, Bautsch W. Eur. J. Immunol. 26, 1944-50, (1996). View articlePMID: 8765043

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