Complement Anaphylatoxin
Many small fragments with biological activity are produced during the activation of the complement cascade, including strong chemotactic agents and secretagogues that act on immune and non-immune cells. Because they can affect the release of histamine from mast cells, they are called anaphylatoxin at first, and they are subsequently reclassified as complement component peptides. Anaphylatoxin includes C3a and C5a, and their effects involve immune response, neural development and organ regeneration. C4a is a weakly active anaphylatoxin, which has a similar structure to C3a and C5a, but has no activity in humans. Since the main function of anaphylatoxin is inflammation, they are important targets for the development of anti-inflammatory therapies.
Anaphylatoxin Receptors
Anaphylatoxin receptors (also known as complement peptide receptors) are a group of G protein-coupled receptors (GPCRs). Its members include C3a receptor (C3AR1), C5a receptor (C5AR1) and C5L2 (C5AR2). Among them, C3AR1 and C5AR1 receptors are both classic GPCRs, but C5AR2 is permanently uncoupled from G protein and can be linked to β-arrestin. Studies have shown that activation of C5AR1 and C5AR2 in mice is necessary for a complete pro-inflammatory response. Several receptor antagonists of anaphylatoxin have been reported, but so far none have been effective in humans.
Fig.1 Schematic of the human complement anaphylatoxin receptor structure. (Barnum, 2015)
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C3a Receptor (C3AR1)
C3a receptor is a G protein-coupled receptor, also known as complement component 3a receptor 1 (i.e. C3AR1). The protein participates in the activity of the complement system, and through binding with complement component C3a, it then regulates the body's immune response, diet-induced obesity, arthritis and cancer, etc. C3aR is expressed in various cells and tissues such as neutrophils, eosinophils, basophils, mast cells and monocytes / macrophages. C3aR and C5aR conformations will change through binding to the ligand, especially through interaction with boxed residues, leading to the activation of the heterotrimeric G protein. Subsequently, PLC, PI-3K, PKC, PKB, MAPK and other intracellular kinases and Ras, Rac, Rho, Cdc42 and other small G proteins will be activated, eventually leading to a variety of biological effects.
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Receptors for C5a
C5a has two receptors, C5aR (also known as CD88) and C5L2 (that is, C5a2 or GPR77). The former was cloned in 1991 and the latter was identified in 2000. C5aR belongs to the peptide receptor subfamily of class A rhodopsin-like receptors. A small amount of single nucleotide polymorphisms (SNPs) were found in the genes of both receptors. No association has been found between these SNPs and human diseases. C5aR or C5L2 gene-deficient mice do not have survival problems, but changes have occurred in many diseases involving C5a. The absence of C5aR indicates the receptor's role in contact sensitivity, glomerulonephritis, pulmonary hypersensitivity, which are in response to mycobacterial infection and in mast cell-mediated neutrophil accumulation in peritonitis. However, the lack of C5aR had little effect on the course of experimental autoimmune encephalomyelitis. After attacking the lungs of C5aR-deficient mice with allergens, it was found that Th2 cytokine levels increased significantly, serum IgE levels also increased, and inflammatory cells were also recruited in large numbers. In addition, studies have shown that the lack of C5L2 can enhance the body's response to C5a, but it can reduce the response of neutrophils to C5a in vitro. These all indicate that the receptor has multiple effects.
Fig. 2 Schematic representation of complement C5a receptors (C5aRs).2
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Reference
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Barnum, Scott R. "C4a: an anaphylatoxin in name only." Journal of innate immunity 7.4 (2015): 333-339.
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From Wikipedia: By Kohidai, L., CC BY-SA 3.0 https://commons.wikimedia.org/wiki/File:C5a-receptor.png
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