C5AR1

Official Full Name

complement C5a receptor 1

Organism

Homo sapiens

GeneID

728

Background

Enables G protein-coupled receptor activity and complement component C5a receptor activity. Involved in several processes, including complement component C5a signaling pathway; mRNA transcription by RNA polymerase II; and positive regulation of ERK1 and ERK2 cascade. Located in apical part of cell and basolateral plasma membrane. Biomarker of Alzheimer's disease; asthma; chronic obstructive pulmonary disease; rhinitis; and severe acute respiratory syndrome. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

C5A; C5AR; C5R1; CD88;

Bio Chemical Class

GPCR rhodopsin

Protein Sequence

MDSFNYTTPDYGHYDDKDTLDLNTPVDKTSNTLRVPDILALVIFAVVFLVGVLGNALVVWVTAFEAKRTINAIWFLNLAVADFLSCLALPILFTSIVQHHHWPFGGAACSILPSLILLNMYASILLLATISADRFLLVFKPIWCQNFRGAGLAWIACAVAWGLALLLTIPSFLYRVVREEYFPPKVLCGVDYSHDKRRERAVAIVRLVLGFLWPLLTLTICYTFILLRTWSRRATRSTKTLKVVVAVVASFFIFWLPYQVTGIMMSFLEPSSPTFLLLKKLDSLCVSFAYINCCINPIIYVVAGQGFQGRLRKSLPSLLRNVLTEESVVRESKSFTRSTVDTMAQKTQAV

Open

Disease

Atopic eczema, Central nervous system disease, Haemolytic anemia, Postoperative inflammation, Rheumatoid arthritis, Vasculitis

Approved Drug

1 +

Clinical Trial Drug

2 +

Discontinued Drug

2 +

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Detailed Information

The C5AR1 gene, known for its involvement in numerous critical biological processes, encodes the Complement C5a Receptor 1, a significant player in the immune response. Mostly expressed in many immune cells including neutrophils, macrophages, and mast cells, this receptor functions mostly as a G protein-coupled receptor (GPCR). Knowing the processes and pathways connected with C5AR1 not only improves our knowledge of immune function but also provides an understanding of its possible therapeutic target in numerous disorders, including cancer, chronic respiratory diseases, and neurodegenerative diseases.

Functional Role and Signaling Mechanisms of C5AR1

The C5AR1 receptor mostly binds the anaphylatoxin C5a, a strong chemotactic agent essential for organizing inflammatory reactions. C5AR1 experiences a conformational shift upon binding to C5a, therefore activating many downstream signaling channels. All of these contribute to the inflammatory process including increased intracellular calcium levels, chemotaxis, granule enzyme release, and superoxide anion synthesis resulting from this activation. Strategically placed in the basolateral plasma membrane and the apical section of the cell, the receptor enables its contact with ligands and so generates signaling cascades.

Starting the complement cascade, a crucial part of both the innate and adaptive immune systems depends on the C5a-C5AR1 axis. This cascade boosts phagocytosis, lysing of pathogens, and starts inflammatory reactions among other immune processes. Underlining its importance in health and illness, deregulation of C5AR1 activity might result in many clinical states given the complicated interaction among these systems.

Figure 1 describes how C5a/C5aR1 signaling contributes to colorectal tumorigenesis by recruiting MDSCs and modulating cytokine production, thereby impairing CD8+ T cell function and promoting tumor development. Figure 1. Schematic illustrating how C5a/C5aR1 signaling drives colorectal tumorigenesis by altering immune responses. (Ding P, et al., 2020)

C5AR1 in Disease Contexts

C5AR1 is recognized as a biomarker for several diseases, including Alzheimer's disease, asthma, chronic obstructive pulmonary disease, and severe acute respiratory syndrome (SARS). Its role in these conditions underscores the potential for targeting C5AR1 in therapeutic interventions. For instance, in Alzheimer’s disease, C5AR1 activation may exacerbate neuroinflammation, leading to neuronal damage and cognitive decline. Similarly, in respiratory conditions like asthma and COPD, the C5a-C5AR1 interaction may contribute to airway hyperresponsiveness and inflammation, highlighting the importance of this receptor in managing respiratory health.

Moreover, the complement C5a receptor's involvement extends to cancer, particularly in the recruitment of myeloid-derived suppressor cells (MDSCs) to the tumor microenvironment. C5a acts as a chemotactic factor, drawing MDSCs and other immunosuppressive cells to the tumor site, where they facilitate tumor progression and metastasis. By inhibiting T cell activation and promoting an immunosuppressive milieu, C5AR1 enhances tumor survival and growth, making it a compelling target for cancer therapies.

Therapeutic Strategies Targeting C5AR1

Targeting the C5a-C5AR1 axis has become a viable therapeutic approach considering its central involvement in many illnesses. Several strategies have been developed including small compounds, C5aR1 antibodies, and C5a antagonists. Especially the anti-C5 antibody eculizumab and its derivative Ravulizumab have attracted interest for their capacity to reduce C5 activity, hence stopping C5a production and consequent receptor activation. These treatments could thus unintentionally inhibit the development of the membrane attack complex (MAC), therefore upsetting the protective action of the complement system.

Targeting C5AR1 directly, on the other hand, could provide a more complex strategy that preserves important complement activities and reduces too much inflammation. Avacopan and small-molecule antagonists are under research for their capacity to block C5AR1 signaling without interfering with the more general protective functions of the complement cascade. These approaches emphasize the therapeutic possibilities of targeting C5AR1 because they show major progress in treating inflammatory illnesses.

Knowing the structural foundation of C5AR1 activation helps one to better appreciate its possible use as a therapeutic target and basis. Recent experiments have shown that C5a interacts with C5AR1 causes significant conformational changes in the receptor. Important structural elements of GPCR activation include the outward migration of transmembrane domain 6 (TM6) and the reorganization of TM3 and TM7. These modifications improve the orthosteric binding volume of the receptor and help to connect with G proteins, hence starting downstream signaling cascades.

Furthermore stressing the significance of certain residues in the activation process is the structural study. For example, by upsetting intramolecular interactions that stabilize the inactive state of C5AR1, mutations at sites inside the zipper motif greatly affect receptor activation. These revelations highlight the dynamic character of C5AR1 and its ligand adaptation, which might guide the creation of more potent receptor modulators.

References:

Feng Y, Zhao C, Deng Y, et al. Mechanism of activation and biased signaling in complement receptor C5aR1. Cell Res. 2023;33(4):312-324.
Li X, Poire A, Jeong KJ, et al. C5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer. Nat Commun. 2024;15(1):4485.
Ding P, Xu Y, Li L, et al. Intracellular complement C5a/C5aR1 stabilizes β-catenin to promote colorectal tumorigenesis. Cell Rep. 2022;39(9):110851.
Ding P, Li L, Li L, et al. C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation. Theranostics. 2020 Jul 9;10(19):8619-8632

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