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C5a2 receptor

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Target id: 33

Nomenclature: C5a2 receptor

Family: Complement peptide receptors

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 337 19q13.32 C5AR2 complement C5a receptor 2
Mouse 7 344 7 A2 C5ar2 complement component 5a receptor 2
Rat 7 343 1q21 C5ar2 complement C5a receptor 2
Previous and Unofficial Names Click here for help
C5L2 | C5A receptor beta | complement 5A receptor beta | G protein-coupled receptor 77 | GPR77 | complement component 5a receptor 2
Database Links Click here for help
Specialist databases
GPCRdb c5ar2_human (Hs), c5ar2_mouse (Mm), c5ar2_rat (Rn)
Other databases
Alphafold
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands Click here for help
C5a {Sp: Human}
C5a des-Arg {Sp: Human}

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Agonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
P59 [PMID: 27108698] Peptide Hs Biased agonist 4.2 pKi 5
pKi 4.2 (Ki 6.4x10-5 M) Exhibits selective partial agonism for recruitment of β-arrestin 2 via C5aR2 in a BRET C5aR2-β-arrestin 2 recruitment assay [5]
Description: Binding assay
P32 [PMID: 27108698] Peptide Hs Biased agonist 3.7 pKi 5
pKi 3.7 (Ki 2.23x10-4 M) Exhibits selective partial agonism for recruitment of β-arrestin 2 via C5aR2 in a BRET C5aR2-β-arrestin 2 recruitment assay [5]
Description: Binding assay
C5a {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Immunopharmacology Ligand Hs Full agonist 8.9 pEC50 2
pEC50 8.9 (EC50 1.4x10-9 M) [2]
C5a des-Arg {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 8.6 pEC50
pEC50 8.6 (EC50 2.3x10-9 M)
C5apep Peptide Hs Partial agonist 6.2 pEC50 18
pEC50 6.2 (EC50 7.09x10-7 M) [18]
Description: β-arrestin recruitment determined in a BRET assay
C5a {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Immunopharmacology Ligand Hs Full agonist 8.0 – 8.6 pIC50 2,15
pIC50 8.0 – 8.6 (IC50 9.5x10-9 – 2.5x10-9 M) [2,15]
C5a des-Arg {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Agonist 7.4 – 7.9 pIC50 2,15
pIC50 7.4 – 7.9 (IC50 3.65x10-8 – 1.2x10-8 M) [2,15]
C5a hexapeptide analogue Peptide Hs Agonist 4.7 pIC50 15
pIC50 4.7 (IC50 1.8x10-5 M) [15]
[125I]C5a (human) Peptide Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Full agonist - -
Eu-DTPA-[Ser27, Nle70]hC5a Peptide Click here for species-specific activity table Ligand is labelled Hs Agonist - - 9
[9]
Agonist Comments
pEC50 values for C5a and C5a des Arg are from unpublished data. Rodent C5a2 seems to have an even stronger preference for C5a des Arg over C5a [21].
Antagonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CHIPS-(28-149) Peptide Hs Antagonist 6.6 pIC50 25
pIC50 6.6 (IC50 2.74x10-7 M) [25]
A8Δ71-73 Peptide Click here for species-specific activity table Mm Antagonist ~6.0 pIC50 16
pIC50 ~6.0 (IC50 ~1x10-6 M) [16]
View species-specific antagonist tables
Antagonist Comments
CHIPS-(28-149) inhibits the binding of C5a des Arg but not C5a [25].
Immunopharmacology Comments
C5aR is typically associated with the compement cascade and innate immunity. However, the complement C5a receptor 2 may act as a decoy receptor for C5a, as it has no reported G protein signalling capacity.
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Immune regulation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Other - See Comments
Comments:  No G protein coupling is observed for wild type C5a2. C5a2 is constitutively coupled to β-arrestin 2 although the degree of coupling is increased by both C5a and C5a des-Arg. β-arrestin 2 is preferentially bound by C5a2 in the presence of C5a1, probably as a consequence of the dimerisation of these two receptors [1,4,11,23].
References: 
Tissue Distribution Click here for help
Kidney
Species:  Human
Technique:  Immunohistochemistry
References:  24
Leukocytes, spleen, testis
Species:  Human
Technique:  Northern blot
References:  14
Brain, liver
Species:  Human
Technique:  Northern blot
References:  12
Brain
Species:  Rat
Technique:  in situ hybridisation
References:  12
Expression Datasets Click here for help

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays Click here for help
Suppression of C5a1 responses
Species:  Human
Tissue:  Blood mononuclear cells
Response measured:  IL-8 secretion
References:  19
Suppression of Th2 cytokine production
Species:  Mouse
Tissue:  Myeloid dendritic cells
Response measured:  IL-23 production
References:  26
Arrestin association
Species:  Human
Tissue:  Transfected CHO cells
Response measured:  Increase in beta-galactosidase activity due to the assembly of a functional enzyme when C5a2 and arrestin are in close proximity
References:  1,6,11,23
HMGB1 production
Species:  Mouse
Tissue:  Macrophages
Response measured:  HMGB1 secretion
References:  20
Uptake of C5a
Species:  Human
Tissue:  Leukocytes
Response measured:  Loss of extracellular C5a and increased intracellular accumulation
References:  22
Physiological Functions Click here for help
Uptake of C5a
Species:  Human
Tissue:  Leukocytes
References:  22
Stimulation of triglyceride production
Species:  Human
Tissue:  Adipose
References:  10-11
Suppression of Th2 cytokine production
Species:  Mouse
Tissue:  Myeloid dendritic cells
References:  26
Suppression of C5a1 responses
Species:  Human
Tissue:  Blood mononuclear cells
References:  19
Physiological Consequences of Altering Gene Expression Click here for help
Enhancement of biological activity of C5a1 resulting in enhanced immune complex injury
Species:  Mouse
Tissue:  Pulmonary
Technique:  Targeting in embryonic stem cells
References:  8
Increased NFκB activation, increased inflammation
Species:  Rat
Tissue:  Astrocytes
Technique:  RNA interference (RNAi)
References:  7
Decreased signalling in response to C5a resulting in hypersensitivity to spetic shock, reduced airway hyper-responsiveness
Species:  Mouse
Tissue:  Leuokocytes
Technique:  Targeting in embryonic stem cells
References:  3,20
Lower triglyceride synthesis resulting in hyperphagy
Species:  Mouse
Tissue:  Adipose
Technique:  Targeting in embryonic stem cells
References:  17
Protection from airway hyper-responsiveness resulting in smaller response to house dust mite and ovalbumin-induced experimental allergic asthma
Species:  Mouse
Tissue:  Pulmonary
Technique:  Targeting in embryonic stem cells
References:  26
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Gpr77tm1Gdy Gpr77tm1Gdy/Gpr77tm1Gdy
involves: 129 * C57BL/6
MGI:2442013  MP:0005666 abnormal adipose tissue physiology PMID: 17641279 
Gpr77tm1Gdy Gpr77tm1Gdy/Gpr77tm1Gdy
involves: 129 * C57BL/6
MGI:2442013  MP:0002954 abnormal aerobic energy metabolism PMID: 17641279 
Gpr77tm1Gdy Gpr77tm1Gdy/Gpr77tm1Gdy
involves: 129 * C57BL/6
MGI:2442013  MP:0009115 abnormal fat cell morphology PMID: 17641279 
Gpr77tm1Gdy Gpr77tm1Gdy/Gpr77tm1Gdy
involves: 129 * C57BL/6
MGI:2442013  MP:0002078 abnormal glucose homeostasis PMID: 17641279 
Gpr77tm1Cge Gpr77tm1Cge/Gpr77tm1Cge
B6.129S1-Gpr77
MGI:2442013  MP:0001819 abnormal immune cell physiology PMID: 16204243 
Gpr77tm1Gdy Gpr77tm1Gdy/Gpr77tm1Gdy
involves: 129 * C57BL/6
MGI:2442013  MP:0002079 increased circulating insulin level PMID: 17641279 
Gpr77tm1Gdy Gpr77tm1Gdy/Gpr77tm1Gdy
involves: 129 * C57BL/6
MGI:2442013  MP:0003909 increased eating behavior PMID: 17641279 
Gpr77tm1Cge Gpr77tm1Cge/Gpr77tm1Cge
B6.129S1-Gpr77
MGI:2442013  MP:0001846 increased inflammatory response PMID: 16204243 
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Coronary artery disease
Disease Ontology: DOID:3393
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human P233L 28
Disease:  Diabetes mellitus, noninsulin-dependent; NIDDM
Synonyms: Diabetes mellitus, Type II; T2D [OMIM: 125853]
Maturity onset diabetes
Type 2 diabetes mellitus [Disease Ontology: DOID:9352]
Disease Ontology: DOID:9352
OMIM: 125853
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human P233L 29
Disease:  Familial combined hyperlipidemia
Disease Ontology: DOID:13809
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human S323I 13,27
General Comments
Binds C5a complement factor, but appears to lack G protein signalling and has been termed a decoy receptor [22]. There remains controversy regarding the ligands (especially C3a des Arg), function (C3a des Arg-mediated control of triglyceride synthesis) and whether it is pro- or anti-inflammatory.

References

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1. 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]

2. 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]

3. Chen NJ, Mirtsos C, Suh D, Lu YC, Lin WJ, McKerlie C, Lee T, Baribault H, Tian H, Yeh WC. (2007) C5L2 is critical for the biological activities of the anaphylatoxins C5a and C3a. Nature, 446 (7132): 203-7. [PMID:17322907]

4. 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]

5. 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]

6. Discoverx. G-Protein Coupled Receptor 77 (C5L2). Accessed on 24/01/2013. Modified on 24/01/2013. Discoverx, http://www.discoverx.com/target-data-sheets/gpcr/c5l2#

7. 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]

8. Gerard NP, Lu B, Liu P, Craig S, Fujiwara Y, Okinaga S, Gerard C. (2005) An anti-inflammatory function for the complement anaphylatoxin C5a-binding protein, C5L2. J Biol Chem, 280 (48): 39677-80. [PMID:16204243]

9. Gorlov IP, Kamat A, Bogatcheva NV, Jones E, Lamb DJ, Truong A, Bishop CE, McElreavey K, Agoulnik AI. (2002) Mutations of the GREAT gene cause cryptorchidism. Hum Mol Genet, 11 (19): 2309-18. [PMID:12217959]

10. 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]

11. 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]

12. Lee DK, George SR, Cheng R, Nguyen T, Liu Y, Brown M, Lynch KR, O'Dowd BF. (2001) Identification of four novel human G protein-coupled receptors expressed in the brain. Brain Res Mol Brain Res, 86 (1-2): 13-22. [PMID:11165367]

13. Marcil M, Vu H, Cui W, Dastani Z, Engert JC, Gaudet D, Castro-Cabezas M, Sniderman AD, Genest J, Cianflone K. (2006) Identification of a novel C5L2 variant (S323I) in a French Canadian family with familial combined hyperlipemia. Arterioscler Thromb Vasc Biol, 26 (7): 1619-25. [PMID:16627811]

14. Ohno M, Hirata T, Enomoto M, Araki T, Ishimaru H, Takahashi TA. (2000) A putative chemoattractant receptor, C5L2, is expressed in granulocyte and immature dendritic cells, but not in mature dendritic cells. Mol Immunol, 37 (8): 407-12. [PMID:11090875]

15. 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]

16. Otto M, Hawlisch H, Monk PN, Müller M, Klos A, Karp CL, Köhl J. (2004) C5a mutants are potent antagonists of the C5a receptor (CD88) and of C5L2: position 69 is the locus that determines agonism or antagonism. J Biol Chem, 279 (1): 142-51. [PMID:14570896]

17. Paglialunga S, Schrauwen P, Roy C, Moonen-Kornips E, Lu H, Hesselink MK, Deshaies Y, Richard D, Cianflone K. (2007) Reduced adipose tissue triglyceride synthesis and increased muscle fatty acid oxidation in C5L2 knockout mice. J Endocrinol, 194 (2): 293-304. [PMID:17641279]

18. Pandey S, Li XX, Srivastava A, Baidya M, Kumari P, Dwivedi H, Chaturvedi M, Ghosh E, Woodruff TM, Shukla AK. (2019) Partial ligand-receptor engagement yields functional bias at the human complement receptor, C5aR1. J Biol Chem, 294 (24): 9416-9429. [PMID:31036565]

19. Raby AC, Holst B, Davies J, Colmont C, Laumonnier Y, Coles B, Shah S, Hall J, Topley N, Köhl J et al.. (2011) TLR activation enhances C5a-induced pro-inflammatory responses by negatively modulating the second C5a receptor, C5L2. Eur J Immunol, 41 (9): 2741-52. [PMID:21630250]

20. Rittirsch D, Flierl MA, Nadeau BA, Day DE, Huber-Lang M, Mackay CR, Zetoune FS, Gerard NP, Cianflone K, Köhl J et al.. (2008) Functional roles for C5a receptors in sepsis. Nat Med, 14 (5): 551-7. [PMID:18454156]

21. Scola AM, Higginbottom A, Partridge LJ, Reid RC, Woodruff T, Taylor SM, Fairlie DP, Monk PN. (2007) The role of the N-terminal domain of the complement fragment receptor C5L2 in ligand binding. J Biol Chem, 282 (6): 3664-71. [PMID:17158873]

22. 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]

23. 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]

24. van Werkhoven MB, Damman J, Daha MR, Krikke C, van Goor H, van Son WJ, Hillebrands JL, van Dijk MC, Seelen MA. (2013) Novel insights in localization and expression levels of C5aR and C5L2 under native and post-transplant conditions in the kidney. Mol Immunol, 53 (3): 237-45. [PMID:22960554]

25. Wright AJ, Higginbottom A, Philippe D, Upadhyay A, Bagby S, Read RC, Monk PN, Partridge LJ. (2007) Characterisation of receptor binding by the chemotaxis inhibitory protein of Staphylococcus aureus and the effects of the host immune response. Mol Immunol, 44 (10): 2507-17. [PMID:17258808]

26. Zhang X, Schmudde I, Laumonnier Y, Pandey MK, Clark JR, König P, Gerard NP, Gerard C, Wills-Karp M, Köhl J. (2010) A critical role for C5L2 in the pathogenesis of experimental allergic asthma. J Immunol, 185 (11): 6741-52. [PMID:20974988]

27. Zheng YY, Xie X, Ma YT, Yang YN, Fu ZY, Li XM, Liu F, Yang SJ, Ma X, Chen BD. (2011) S323I polymorphism of the C5L2 gene was not identified in a Chinese population with familial combined hyperlipidemia or with type 2 diabetes. Genet Mol Res, 10 (4): 3256-66. [PMID:22194190]

28. Zheng YY, Xie X, Ma YT, Yang YN, Fu ZY, Li XM, Ma X, Chen BD, Liu F. (2011) Relationship between a novel polymorphism of the C5L2 gene and coronary artery disease. PLoS ONE, 6 (6): e20984. [PMID:21698200]

29. Zheng YY, Xie X, Ma YT, Yang YN, Fu ZY, Li XM, Ma X, Chen BD, Liu F. (2012) Relationship between type 2 diabetes mellitus and a novel polymorphism C698T in C5L2 in the Chinese Han population. Endocrine, 41 (2): 296-301. [PMID:22180093]

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