C5AR1

C5AR1 Full Name

Complement Component C5a R1

C5AR1 Introduction

Complement Component 5a Receptor 1 (C5AR1) is a vital G-protein-coupled receptor (GPCR) that serves as the primary cell surface receptor for complement component 5a (C5a), a potent pro-inflammatory anaphylatoxin generated during complement system activation. Encoded by the C5AR1 gene located on human chromosome 19q13.32, this seven-transmembrane receptor is abundantly and selectively expressed on innate immune cells including neutrophils, monocytes, macrophages, and dendritic cells, as well as on epithelial, endothelial, and neuronal cells under inflammatory conditions. As a core upstream regulator of complement-mediated immune responses, C5AR1 specifically binds to activated C5a ligand to trigger downstream intracellular signaling cascades that drive immune cell activation, chemotaxis, and inflammatory mediator release. The C5a-C5AR1 axis is widely recognized as a central bridge connecting innate immunity, systemic inflammation, and tissue injury. Accumulating high-quality biomedical studies have verified that abnormal activation or dysregulated expression of C5AR1 is closely associated with acute and chronic inflammatory diseases, autoimmune disorders, infectious injuries, and tumor microenvironment remodeling, making C5AR1 a critical immune regulatory gene and a promising targeted therapeutic biomarker for multiple human diseases.

Figure 1. Revealing the signaling of complement receptors C3aR and C5aR1 by anaphylatoxins C5AR1.(Wang Y, et al. 2023)

Structural Characteristics and Ligand Binding Mechanism of C5AR1
C5AR1 belongs to the class A GPCR superfamily and possesses a canonical seven-transmembrane alpha-helix structural topology, with an extracellular N-terminal domain, three extracellular loops, three intracellular loops, and a cytoplasmic C-terminal tail that together support its ligand binding and signal transduction functions. The extracellular domain of C5AR1 contains specific glycosylation sites and ligand recognition motifs that enable high-affinity and high-specificity binding to mature C5a, the active cleavage product of complement protein C5, while excluding binding to inactive C5 precursor and other complement fragments. Upon C5a ligand ligation, C5AR1 undergoes rapid conformational rearrangement, which promotes the dissociation of coupled heterotrimeric G proteins and initiates downstream signaling pathways including PI3K/Akt, MAPK, and NF-κB cascades. The intracellular C-terminal tail of C5AR1 mediates receptor phosphorylation, desensitization, and internalization, forming a negative feedback mechanism that precisely controls the duration and intensity of inflammatory signaling. This sophisticated structural and regulatory mechanism ensures that C5AR1-mediated immune responses are rapidly activated upon pathogen stimulation and timely terminated to avoid excessive tissue inflammation and damage.

Pathophysiological and Clinical Significance of C5AR1
Sustained overactivation, aberrant expression, or dysregulated signaling of C5AR1 is a key driving factor for the progression of numerous inflammatory, autoimmune, infectious, and malignant diseases, possessing important clinical diagnostic and therapeutic significance. In systemic inflammatory disorders, excessive C5AR1 activation triggers persistent immune cell infiltration and massive pro-inflammatory cytokine release, exacerbating tissue damage in sepsis, acute lung injury, rheumatoid arthritis, and inflammatory bowel disease. In autoimmune diseases, abnormal C5AR1 signaling amplifies self-immune responses, promotes autoantibody production, and aggravates tissue autoimmune injury. In tumor biology, C5AR1 is frequently overexpressed in various solid tumors, including lung cancer, colorectal cancer, breast cancer, and hepatocellular carcinoma; C5AR1-mediated inflammatory signaling remodels the tumor immunosuppressive microenvironment, promotes tumor cell proliferation, invasion, metastasis, and angiogenesis, and accelerates tumor immune escape. Clinically, C5AR1 expression levels are closely correlated with disease severity, inflammatory activity, and tumor prognosis, and targeted inhibition of the C5a-C5AR1 axis has become a novel and hot therapeutic strategy for treating refractory inflammatory diseases and malignant tumors in clinical translational research.

Alternate Names for C5AR1

C5a anaphylatoxin chemotactic receptor; C5A; C5aR; C5a-R; C5AR1; C5ARC5a anaphylatoxin receptor; C5R1C5a ligand; CD88 antigen; CD88; complement component 5 receptor 1 (C5a ligand); complement component 5 receptor 1; complement component 5a receptor 1; Complement Component C5a R1; Complement Component C5aR1

• 1.Wang Y, Liu W, Xu Y, et al. Revealing the signaling of complement receptors C3aR and C5aR1 by anaphylatoxins. Nature Chemical Biology, 2023, 19(11): 1351-1360.