C5a<sub>2</sub> receptor | Complement peptide receptors | IUPHAR/BPS Guide to PHARMACOLOGY

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C5a2 receptor

Target id: 33

Nomenclature: C5a2 receptor

Family: Complement peptide receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: OFF :     C5a2 receptor has curated data in GtoImmuPdb

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 337 19q13.33 C5AR2 complement component 5a receptor 2
Mouse 7 344 7A27 C5ar2 complement component 5a receptor 2
Rat 7 343 1 C5ar2 complement component 5a receptor 2
Previous and Unofficial Names
C5L2 | C5A receptor beta | complement 5A receptor beta | G protein-coupled receptor 77 | GPR77
Database Links
Specialist databases
GPCRDB c5ar2_human (Hs), c5ar2_mouse (Mm), c5ar2_rat (Rn)
Other databases
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Reference
P59 [PMID: 27108698] 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] 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} Hs Full agonist 8.9 pEC50
pEC50 8.9 (EC50 1.4x10-9 M)
C5a des-Arg {Sp: Human} Hs Full agonist 8.6 pEC50
pEC50 8.6 (EC50 2.3x10-9 M)
C5a {Sp: Human} Hs Full agonist 8.0 – 8.6 pIC50 2,14
pIC50 8.0 – 8.6 (IC50 9.5x10-9 – 2.5x10-9 M) [2,14]
C5a des-Arg {Sp: Human} Hs Agonist 7.4 – 7.9 pIC50 2,14
pIC50 7.4 – 7.9 (IC50 3.65x10-8 – 1.2x10-8 M) [2,14]
C5a hexapeptide analogue Hs Agonist 4.7 pIC50 14
pIC50 4.7 (IC50 1.8x10-5 M) [14]
[125I]C5a (human) Hs Full agonist - -
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pEC50 values for C5a and C5a des Arg are from unpublished data.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 [19].
Antagonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Reference
CHIPS-(28-149) Hs Antagonist 6.6 pIC50 23
pIC50 6.6 (IC50 2.74x10-7 M) [23]
A8Δ71-73 Mm Antagonist ~6.0 pIC50 15
pIC50 ~6.0 (IC50 ~1x10-6 M) [15]
View species-specific antagonist tables
Antagonist Comments
CHIPS-(28-149) inhibits the binding of C5a des Arg but not C5a [23].
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
GO Annotations:  Associated to 3 GO processes
GO:0006954 inflammatory response IBA
GO:0030449 regulation of complement activation TAS
GO:0090024 negative regulation of neutrophil chemotaxis IMP
Immuno Process:  Immune regulation
GO Annotations:  Associated to 3 GO processes
GO:0004878 complement component C5a receptor activity IBA
GO:0030449 regulation of complement activation TAS
GO:0090024 negative regulation of neutrophil chemotaxis IMP
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 3 GO processes
GO:0032720 negative regulation of tumor necrosis factor production IMP
GO:1900165 negative regulation of interleukin-6 secretion IMP
GO:2000482 regulation of interleukin-8 secretion IMP
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 1 GO processes
GO:0090024 negative regulation of neutrophil chemotaxis IMP
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0004878 complement component C5a receptor activity IBA
Primary Transduction Mechanisms
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 [1,4,10,21].
References: 
Tissue Distribution
Leukocytes, spleen, testis
Species:  Human
Technique:  Northern blot
References:  13
Brain, liver
Species:  Human
Technique:  Northern blot
References:  11
Kidney
Species:  Human
Technique:  Immunohistochemistry
References:  22
Brain
Species:  Rat
Technique:  in situ hybridisation
References:  11
Expression Datasets

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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
Suppression of Th2 cytokine production
Species:  Mouse
Tissue:  Myeloid dendritic cells
Response measured:  IL-23 production
References:  24
Uptake of C5a
Species:  Human
Tissue:  Leukocytes
Response measured:  Loss of extracellular C5a and increased intracellular accumulation
References:  20
Suppression of C5a1 responses
Species:  Human
Tissue:  Blood mononuclear cells
Response measured:  IL-8 secretion
References:  17
HMGB1 production
Species:  Mouse
Tissue:  Macrophages
Response measured:  HMGB1 secretion
References:  18
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:  1,6,10,21
Physiological Functions
Uptake of C5a
Species:  Human
Tissue:  Leukocytes
References:  20
Suppression of Th2 cytokine production
Species:  Mouse
Tissue:  Myeloid dendritic cells
References:  24
Suppression of C5a1 responses
Species:  Human
Tissue:  Blood mononuclear cells
References:  17
Stimulation of triglyceride production
Species:  Human
Tissue:  Adipose
References:  9-10
Physiological Consequences of Altering Gene Expression
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:  3,18
Lower triglyceride synthesis resulting in hyperphagy
Species:  Mouse
Tissue:  Adipose
Technique:  Targeting in embryonic stem cells
References:  16
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:  24
Phenotypes, Alleles and Disease Models 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
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 26
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 27
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 12,25
General Comments
Binds C5a complement factor, but appears to lack G protein signalling and has been termed a decoy receptor [20]. 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. 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]

10. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

18. 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]

19. 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]

20. 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]

21. 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]

22. 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]

23. 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]

24. 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]

25. 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]

26. 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]

27. 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]

Contributors

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How to cite this page

Peter Monk.
Complement peptide receptors: C5a2 receptor. Last modified on 19/02/2018. Accessed on 21/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=33.