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C5AR1  -  complement component 5a receptor 1

Homo sapiens

Synonyms: C5A, C5AR, C5R1, C5a anaphylatoxin chemotactic receptor, C5a anaphylatoxin chemotactic receptor 1, ...
 
 
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Disease relevance of C5AR1

 

Psychiatry related information on C5AR1

  • These results have implications for understanding the role of neuronal C5aR receptors in normal neuronal development, neuronal homeostasis, and neuroinflammatory conditions such as Alzheimer's disease [6].
 

High impact information on C5AR1

 

Chemical compound and disease context of C5AR1

 

Biological context of C5AR1

  • Altogether the results indicate that C5aR activation is able to promote a loose association with beta-arrestins, but phosphorylation of either Ser(334)/Ser(338) or Ser(327)/Ser(338) is necessary and sufficient for the formation of a persistent complex [14].
  • In addition to CD88, the seven-transmembrane receptor C5L2 has recently been found to provide high affinity binding sites for C5a and its desarginated form, C5adesArg74 [15].
  • We have used a collection of 133 functional mutants of the C5a receptor obtained in a mutagenesis screen targeting the intracellular loops and the carboxyl terminus (Matsumoto, M. L., Narzinski, K., Kiser, P. D., Nikiforovich, G. V., and Baranski, T. J. (2007) J. Biol. Chem. 282, 3105-3121) to investigate how specificity is encoded [16].
  • In addition, it was observed that C5aR endocytosis was inhibited by the expression of the dominant negative mutants of dynamin (K44E) and beta-arrestin 1 (beta-arr 1-(319-418)-EGFP) [14].
  • Human chemotaxis receptor genes cluster at 19q13.3-13.4. Characterization of the human C5a receptor gene [17].
 

Anatomical context of C5AR1

 

Associations of C5AR1 with chemical compounds

  • Chimeras were generated between the human anaphylatoxin C3a and C5a receptors (C3aR and C5aR, respectively) to define the structural requirements for ligand binding and discrimination [21].
  • Serine residues in the C5aR C terminus were identified that control the intracellular trafficking of the C5aR-arrestin complex in response to C5a [14].
  • Detailed characterization of the C5a receptor gene reveals a two exon structure, with the 5' untranslated sequence and initiating methionine located in the first exon [17].
  • A peptide based on the NH(2) terminus of the C5aR and sulfated at these two tyrosines, but not its unsulfated analogue or a doubly sulfated control peptide, partially inhibited C5a association with its receptor [10].
  • However, when a cysteine residue is placed on their N terminus they can be trapped by disulfide interchange to specific cysteines in helix III and VI and not to other cysteines, engineered into the C5aR [22].
 

Physical interactions of C5AR1

 

Regulatory relationships of C5AR1

 

Other interactions of C5AR1

  • CD35 and C5aR were not significantly expressed [30].
  • A novel feature of this gene, unlike C5a-R and other G-protein-coupled receptors, is the presence of an extraordinarily large predicted extracellular loop comprised of in excess of 160 amino acid residues between transmembrane domains 4 and 5 [31].
  • The human complement 5a (C5a) anaphylatoxin receptor (CD88) is a G protein-coupled receptor involved in innate host defense and inflammation [14].
  • Human mast cell subsets may also be defined by their expression of receptors such as C5aR and possibly the beta-chemokine receptor CCR3; the CCR3 expression seems to be related to the human mast cell chymase expression [32].
  • Differential regulation of the C3a and C5a receptors (CD88) by IFN-gamma and PMA in U937 cells and related myeloblastic cell lines [33].
 

Analytical, diagnostic and therapeutic context of C5AR1

  • Flow cytometry revealed C5aR (CD88) on approximately 40% memory and 10% naive cells, respectively, whereas GC cells were negative [18].
  • Immunohistochemistry showed that a few CD88+ cells were of the B cell lineage and localized in tonsillar subepithelial areas, where the majority of memory B cells settle [18].
  • Using confocal immunofluorescence microscopy and green fluorescent protein-tagged beta-arrestins (beta-arr 1- and beta-arr 2-EGFP) we show a persistent complex between C5aR and beta-arrestins to endosomal compartments [14].
  • Addressing the molecular mechanism accounting for CD88 receptor antagonism by site-directed mutagenesis, we found that a positively charged amino acid at position 69 is crucial [15].
  • Northern blot analysis revealed that expression of mRNA for this receptor in human tissues, while similar, was distinct from C5a-R expression [31].

References

  1. Human plasmacytoid dendritic cells express receptors for anaphylatoxins c3a and c5a and are chemoattracted to c3a and c5a. Gutzmer, R., K??ther, B., Zwirner, J., Dijkstra, D., Purwar, R., Wittmann, M., Werfel, T. J. Invest. Dermatol. (2006) [Pubmed]
  2. The complement component C5a induces the expression of plasminogen activator inhibitor-1 in human macrophages via NF-kappaB activation. Kastl, S.P., Speidl, W.S., Kaun, C., Rega, G., Assadian, A., Weiss, T.W., Valent, P., Hagmueller, G.W., Maurer, G., Huber, K., Wojta, J. J. Thromb. Haemost. (2006) [Pubmed]
  3. The chemotactic receptor for human C5a anaphylatoxin. Gerard, N.P., Gerard, C. Nature (1991) [Pubmed]
  4. A new staphylococcal anti-inflammatory protein that antagonizes the formyl Peptide receptor-like 1. Prat, C., Bestebroer, J., de Haas, C.J., van Strijp, J.A., van Kessel, K.P. J. Immunol. (2006) [Pubmed]
  5. Expression of cytokines by human astrocytomas following stimulation by C3a and C5a anaphylatoxins: specific increase in interleukin-6 mRNA expression. Sayah, S., Ischenko, A.M., Zhakhov, A., Bonnard, A.S., Fontaine, M. J. Neurochem. (1999) [Pubmed]
  6. Neuronal expression of a functional receptor for the C5a complement activation fragment. O'Barr, S.A., Caguioa, J., Gruol, D., Perkins, G., Ember, J.A., Hugli, T., Cooper, N.R. J. Immunol. (2001) [Pubmed]
  7. C5A anaphylatoxin and its seven transmembrane-segment receptor. Gerard, C., Gerard, N.P. Annu. Rev. Immunol. (1994) [Pubmed]
  8. Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma. Karp, C.L., Grupe, A., Schadt, E., Ewart, S.L., Keane-Moore, M., Cuomo, P.J., Köhl, J., Wahl, L., Kuperman, D., Germer, S., Aud, D., Peltz, G., Wills-Karp, M. Nat. Immunol. (2000) [Pubmed]
  9. Complement anaphylatoxin receptors on neurons: new tricks for old receptors? Nataf, S., Stahel, P.F., Davoust, N., Barnum, S.R. Trends Neurosci. (1999) [Pubmed]
  10. Sulfated tyrosines contribute to the formation of the C5a docking site of the human C5a anaphylatoxin receptor. Farzan, M., Schnitzler, C.E., Vasilieva, N., Leung, D., Kuhn, J., Gerard, C., Gerard, N.P., Choe, H. J. Exp. Med. (2001) [Pubmed]
  11. A potent human C5a receptor antagonist protects against disease pathology in a rat model of inflammatory bowel disease. Woodruff, T.M., Arumugam, T.V., Shiels, I.A., Reid, R.C., Fairlie, D.P., Taylor, S.M. J. Immunol. (2003) [Pubmed]
  12. Inhibition of C5a-induced neutrophil chemotaxis and macrophage cytokine production in vitro by a new C5a receptor antagonist. Haynes, D.R., Harkin, D.G., Bignold, L.P., Hutchens, M.J., Taylor, S.M., Fairlie, D.P. Biochem. Pharmacol. (2000) [Pubmed]
  13. Complement C5a receptor assay for high throughput screening. Harris, S.R., Garlick, R.K., Miller, J.J., Harney, H.N., Monroe, P.J. J. Recept. Res. (1991) [Pubmed]
  14. Phosphorylation of key serine residues is required for internalization of the complement 5a (C5a) anaphylatoxin receptor via a beta-arrestin, dynamin, and clathrin-dependent pathway. Braun, L., Christophe, T., Boulay, F. J. Biol. Chem. (2003) [Pubmed]
  15. 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, P.N., Müller, M., Klos, A., Karp, C.L., Köhl, J. J. Biol. Chem. (2004) [Pubmed]
  16. A Comprehensive Structure-Function Map of the Intracellular Surface of the Human C5a Receptor: II. ELUCIDATION OF G PROTEIN SPECIFICITY DETERMINANTS. Matsumoto, M.L., Narzinski, K., Nikiforovich, G.V., Baranski, T.J. J. Biol. Chem. (2007) [Pubmed]
  17. Human chemotaxis receptor genes cluster at 19q13.3-13.4. Characterization of the human C5a receptor gene. Gerard, N.P., Bao, L., Xiao-Ping, H., Eddy, R.L., Shows, T.B., Gerard, C. Biochemistry (1993) [Pubmed]
  18. rC5a directs the in vitro migration of human memory and naive tonsillar B lymphocytes: implications for B cell trafficking in secondary lymphoid tissues. Ottonello, L., Corcione, A., Tortolina, G., Airoldi, I., Albesiano, E., Favre, A., D'Agostino, R., Malavasi, F., Pistoia, V., Dallegri, F. J. Immunol. (1999) [Pubmed]
  19. Mapping of genes for the human C5a receptor (C5AR), human FMLP receptor (FPR), and two FMLP receptor homologue orphan receptors (FPRH1, FPRH2) to chromosome 19. Bao, L., Gerard, N.P., Eddy, R.L., Shows, T.B., Gerard, C. Genomics (1992) [Pubmed]
  20. Distribution of complement anaphylatoxin receptors and membrane-bound regulators in normal human retina. Vogt, S.D., Barnum, S.R., Curcio, C.A., Read, R.W. Exp. Eye Res. (2006) [Pubmed]
  21. Chimeric receptors of the human C3a receptor and C5a receptor (CD88). Crass, T., Ames, R.S., Sarau, H.M., Tornetta, M.A., Foley, J.J., Köhl, J., Klos, A., Bautsch, W. J. Biol. Chem. (1999) [Pubmed]
  22. Site-specific disulfide capture of agonist and antagonist peptides on the C5a receptor. Buck, E., Bourne, H., Wells, J.A. J. Biol. Chem. (2005) [Pubmed]
  23. G protein-coupled receptor kinases promote phosphorylation and beta-arrestin-mediated internalization of CCR5 homo- and hetero-oligomers. Hüttenrauch, F., Pollok-Kopp, B., Oppermann, M. J. Biol. Chem. (2005) [Pubmed]
  24. Requirements for C5a receptor-mediated IL-4 and IL-13 production and leukotriene C4 generation in human basophils. Eglite, S., Plüss, K., Dahinden, C.A. J. Immunol. (2000) [Pubmed]
  25. Modulation of C3a activity: internalization of the human C3a receptor and its inhibition by C5a. Settmacher, B., Bock, D., Saad, H., Gärtner, S., Rheinheimer, C., Köhl, J., Bautsch, W., Klos, A. J. Immunol. (1999) [Pubmed]
  26. Agonist-dependent phosphorylation of N-formylpeptide and activation peptide from the fifth component of C (C5a) chemoattractant receptors in differentiated HL60 cells. Tardif, M., Mery, L., Brouchon, L., Boulay, F. J. Immunol. (1993) [Pubmed]
  27. Local production of complement proteins in rheumatoid arthritis synovium. Neumann, E., Barnum, S.R., Tarner, I.H., Echols, J., Fleck, M., Judex, M., Kullmann, F., Mountz, J.D., Schölmerich, J., Gay, S., Müller-Ladner, U. Arthritis Rheum. (2002) [Pubmed]
  28. Roles of the ribosomal protein S19 dimer and the C5a receptor in pathophysiological functions of phagocytic leukocytes. Yamamoto, T. Pathol. Int. (2007) [Pubmed]
  29. Antisense knockdown of sphingosine kinase 1 in human macrophages inhibits C5a receptor-dependent signal transduction, Ca2+ signals, enzyme release, cytokine production, and chemotaxis. Melendez, A.J., Ibrahim, F.B. J. Immunol. (2004) [Pubmed]
  30. Expression of complement regulators and receptors on human NT2-N neurons-Effect of hypoxia and reoxygenation. Pedersen, E.D., Frøyland, E., Kvissel, A.K., Pharo, A.M., Skålhegg, B.S., Rootwelt, T., Mollnes, T.E. Mol. Immunol. (2007) [Pubmed]
  31. Molecular cloning and characterization of the human anaphylatoxin C3a receptor. Ames, R.S., Li, Y., Sarau, H.M., Nuthulaganti, P., Foley, J.J., Ellis, C., Zeng, Z., Su, K., Jurewicz, A.J., Hertzberg, R.P., Bergsma, D.J., Kumar, C. J. Biol. Chem. (1996) [Pubmed]
  32. Mast cell granule composition and tissue location--a close correlation. Beil, W.J., Schulz, M., Wefelmeyer, U. Histol. Histopathol. (2000) [Pubmed]
  33. Differential regulation of the C3a and C5a receptors (CD88) by IFN-gamma and PMA in U937 cells and related myeloblastic cell lines. Burg, M., Martin, U., Bock, D., Rheinheimer, C., Köhl, J., Bautsch, W., Klos, A. J. Immunol. (1996) [Pubmed]
 
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