Introduction to anaphylatoxin receptors
Intrigued by the mechanism of anaphylactic shock described in 1902 by Richet and Portier (1), Jules Bordet devoted several experiments to it, in which he showed that anaphylactic shock could be triggered in guinea pigs by intravenous injection of fresh serum previously put in contact with agar, then eliminated by centrifugation.
Bordet hypothesized that anaphylactogenic absorption complexes are thus produced, referring then to the previous works of Friedberger, who had observed a similar phenomenon by injecting fresh serum treated with immune complexes into the animal (2).
As research on complement progressed, researchers discovered the existence of several small aminoterminal cationic fragments resulting from the proteolysis of each of the complement proteins C3, C4 and C5. The C3a, C4a and C5a - 74 to 77 amino acids peptides that are thus derived from enzymatic cleavage - are called anaphylatoxins due to their effect on mast cell histamine release. The most potent of these, C5a, elicits the broadest responses.
Despite relatedness at the genetic level with C3a and C5a, since no specific human C4a receptor has been identified so far, the fact that C4a is anaphylatoxin is highly questionable (3).
C3a and C5a are recognized by specific transmembrane proteins, respectively one C3a receptor, C3aR1 (4,5), and two C5a receptors, C5aR1 and C5aR2, a.k.a CD88 and C5L2 (6,7). They are all members of the rhodopsin-like G-protein coupled receptor (GPCR) family, transducing signals through heterotrimeric G proteins and binding to β-arrestins for internalization (like chemokine receptors CCR5, CXCR1, CXCR2, CXCR4 and CCR7).
GPCR complement 3a receptor 1 (C3AR1)
C3aR tissue expression and distribution
C3aR is highly expressed by granulocytes (eosinophils, basophils) and monocytes (macrophages), CD4+ T lymphocytes, but not on B cells. Many tissues are expressing C3aR (360,000 units per cell in average), and especially spleen, appendix, adipose tissue, spinal cord, lung and placenta (combination of the data from the three transcriptomics datasets HPA, GTEx and FANTOM5 for 55 tissue types and 6 blood cell types).
Structure and ligand interaction of C3aR with C3a
The human C3a receptor (C3aR) is a 54kDa molecule comprising 482 amino acids. It contains an exceptionally large extracellular loop between the fourth and fifth transmembrane domains, and a large second extracellular loop (e2 loop, ∼172 amino acids). Like for CCR5, the analysis of mutant receptors by direct agonist binding assays suggested that e2 loop is necessary for high affinity C3a binding. Both the N- and C-terminal ends of the e2 loop contain anionic residues that may interact with residues in the cationic C3a protein. The equilibrium dissociation constant (Kd) for C3aR is 3.85 ± 0.15 nM, and the interaction with its ligand generates an intracellular calcium flux.