Complement peptide receptors: Introduction

General

The activation of the complement cascade produces a number of small (74-77 amino acid) fragments that are bioactive: potent chemoattractants and secretagogues that act on immune and non-immune cells [21]. Very similar peptides can also be released by the actions of non-complement proteases on the parent molecules, for instance during clotting [1]. Initially termed anaphylatoxins because of their effects on mast cell histamine release, peptides C5a, C3a are now known to act at all levels of the immune response [24] and are also involved in neural development and organ regeneration [6,16]. A peptide with similar structure, C4a, appears to be largely inactive in humans [18]. All three peptides are substrates for highly active carboxypeptidases that cleave the C-terminal arginine residue, forming the more stable des-Arg peptides. The primary function of complement peptides is in inflammation and so they are important targets for the development of anti-inflammatory therapies [16]. Only three receptors for complement peptides have been found in mammals but there are no satisfactory antagonists as yet.

Receptors

The small complement peptide receptor family has not been systematically named until now; the receptor for C3a has been known as C3aR [3,10], whereas the two receptors for C5a have been termed CD88, C5aR, C5R1 for the first to be discovered [12], and C5L2, GPR77 and C5R2 for the second [5]. The subcommittee has decided to re-name these receptors according to IUPHAR guidelines as C3a, C5a1 and C5a2 receptors, respectively (human gene names C3AR, C5AR1 and C5AR2). For the latest IUPHAR review on complement peptide receptor nomenclature and pharmacology see [17]. Phylogenetically, complement peptide receptors are close to the formyl peptide receptor family and more distantly related to the chemokine receptors [13].

Both C3a and C5a1 receptors are classical G protein-coupled receptors, signalling primarily via Gai2 although C5a1 has also been shown to couple to Ga16 [15]. C5a2 appears to be permanently uncoupled from G proteins but can associate with β-arrestin [14]. However, there are several reports that activation of both C5a1 and C5a2 is required for a full pro-inflammatory response, particularly in mice [8]. Signaling through β-arrestin can modulate responses to C3a receptor ligation [30] but has not so far been shown to have much importance for C5a1. Dimerization of C5a1 and C5a2 has recently been demonstrated [25], which may be relevant to the role of C5a2 in the response to C5a.

Pharmacology

The C3a receptor binds only C3a, with no detectable affinity for the metabolite, C3a des-Arg [29]. In contrast, both C5a1 and C5a2 bind both C5a and C5a des-Arg [5]. In most studies, C5a1 has been reported to have a lower affinity for C5a des-Arg, suggesting that des-argination was an inactivation step. However, recent reports have demonstrated that, for some responses, C5a and C5a des-Arg are equipotent, especially when native glycosylated C5a des-Arg is used in preference to recombinant peptide [26].

For all the complement peptides, agonist activity is vested in the C-terminal residues and so short peptide analogs of the C-termini (typically a decapeptide or shorter) have full agonist activity, albeit with a much-reduced potency [9]. These short peptides bind to a receptor site located within the transmembrane (or juxta-membrane) domain of the receptors [20] and there appears to be significant similarity between this domain in C5a1 and C3a receptors, resulting in cross-reactivity of many peptides [4]. Receptor selectivity of the full length peptides is maintained by binding to a second site, located either at the N-terminus (C5a1) or the second extracellular loop (C3a) [7,28]. In contrast few of the peptide analogs binds to C5a2, suggesting that ligand binding is distinctly different for this receptor [27].

Only a single antagonist (SB290157) has been reported for human C3a receptor [2], although this appears to have partial agonist activity in some circumstances [19]. Several C5a1 antagonists have been reported [21], although none have so far been shown to be effective in humans. C5a1 antagonists are typically inactive on rodent receptors, making testing in different disease settings difficult. Only one of these antagonists (A8), derived from the C-terminus of C5a, has been shown to have significant activity at C5a2 [22], making the analysis of the function of this receptor very difficult.

Non-receptor-mediated effects

C4a and C3a (and their des-Arg forms) have potent anti-microbial activity that is independent of receptor binding [23]. C3a is also able to activate certain cell types (e.g. mast cells) by a receptor-independent mechanism, possibly due to the amphipathic nature of this peptide [11].

References

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