C4a: An Anaphylatoxin in Name Only

Abstract

Activation of complement leads to generation of the 3 anaphylatoxins C3a, C4a, and C5a. Although all 3 peptides are structurally similar, only C3a and C5a share a similar functional profile that includes the classic inflammatory activities and, more recently, developmental homing and regenerative properties among others. In contrast, the functional profile of C4a is questionable in most cases owing to contamination of C4a preparations with physiologically relevant levels of C3a and/or C5a. Combined with the absence of an identified C4a receptor and the inability of C4a to signal through the C3a and C5a receptors, it is clear that C4a should not be included in the family of complement anaphylatoxins.

Fig. 1

Schematic of the polypeptide structure of human C3, C4, and C5. a C3 and C5 are composed of an α- and a β-chain that have inter- and intrachain disulfide bridges. C3a and C5a are derived by cleavage of the amino-terminal end of the α-chain by C3/C5 convertases, activated coagulation proteases including thrombin, plasmin, and factors IX through XI, and by bacterial enzymes. b C4 is composed of 3 polypeptide chains (α, β, and γ) which also have inter- and intrachain disulfide bridges. C4a is derived by cleavage of the amino-terminal end of the α-chain by activated C1 on activation of the classical, or by activated mannose binding protein on activation of the lectin pathway. The triangle indicates the relative position of the thioester bond found in the α-chain of C3 and C4.

Fig. 2

Schematic of the human complement anaphylatoxin receptor structure. A schematic structure of the human C3a and C5 receptors is shown. Both receptors are G protein-coupled, 7-membrane-spanning family members. Each transmembrane domain is numbered. The C3aR is unique among GPCRs due to the unusually large extracellular loop between transmembrane domains 4 and 5. The as yet unidentified C4a receptor is shown as partially transparent in the center panel. Shown below the C3aR and C5aR are the relative binding affinities for their known ligands. * The affinity of C5a for both C5aR is in the low nanomolar range. ** The affinity for C5a desArg for C5aR1 is in the low nanomolar range, while the affinity for C5aR2 is in the micromolar range.