Details for: C5AR1

Gene ID: 728

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: C5AR1

Ensembl ID: ENSG00000197405

Description: complement C5a receptor 1

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • CD14-low, CD16-positive monocyte CL0002396
    CSI 43.32
    rCSI 33.38%
    PRS 96.78
  • CD14-positive, CD16-positive monocyte CL0002397
    CSI 19.53
    rCSI 25.59%
    PRS 98.15
  • elicited macrophage CL0000861
    CSI 19.14
    rCSI 17.57%
    PRS 97.44
  • intermediate monocyte CL0002393
    CSI 18.38
    rCSI 27.73%
    PRS 97.27
  • ependymal cell CL0000065
    CSI 14.68
    rCSI 29.79%
    PRS 80.55
  • non-classical monocyte CL0000875
    CSI 13.19
    rCSI 21.15%
    PRS 97.19
  • kidney interstitial alternatively activated macrophage CL1000695
    CSI 10.88
    rCSI 28.37%
    PRS 95.93
  • monocyte CL0000576
    CSI 9.99
    rCSI 18.05%
    PRS 95.53
  • Kupffer cell CL0000091
    CSI 9.05
    rCSI 20.68%
    PRS 95.53
  • CD1c-positive myeloid dendritic cell CL0002399
    CSI 8.94
    rCSI 10.79%
    PRS 97.45
  • macrophage CL0000235
    CSI 8.28
    rCSI 15.05%
    PRS 94.52
  • colon macrophage CL0009038
    CSI 8.01
    rCSI 36.98%
    PRS 98.33
  • Hofbauer cell CL3000001
    CSI 7.61
    rCSI 14.37%
    PRS 97.41
  • mononuclear phagocyte CL0000113
    CSI 7.59
    rCSI 16.7%
    PRS 96.39
  • cardiac muscle cell CL0000746
    CSI 7.39
    rCSI 10.61%
    PRS 88.43
  • lung interstitial macrophage CL4033043
    CSI 7.38
    rCSI 16.56%
    PRS 98.69
  • conventional dendritic cell CL0000990
    CSI 6.91
    rCSI 5.77%
    PRS 88.73
  • alveolar macrophage CL0000583
    CSI 6.59
    rCSI 10.85%
    PRS 95.73
  • CD14-positive, CD16-negative classical monocyte CL0002057
    CSI 6.57
    rCSI 39.77%
    PRS 97.72
  • ciliated cell CL0000064
    CSI 6.5
    rCSI 10.54%
    PRS 89.38
  • CD14-positive monocyte CL0001054
    CSI 6.49
    rCSI 8.09%
    PRS 98.01
  • granulocyte CL0000094
    CSI 6.25
    rCSI 9.56%
    PRS 97
  • myeloid leukocyte CL0000766
    CSI 5.93
    rCSI 5.47%
    PRS 95.59
  • alternatively activated macrophage CL0000890
    CSI 5.85
    rCSI 7.35%
    PRS 97.98
  • myeloid cell CL0000763
    CSI 5.37
    rCSI 22.11%
    PRS 95.44
  • lung macrophage CL1001603
    CSI 5.26
    rCSI 11.74%
    PRS 97.6
  • kidney connecting tubule epithelial cell CL1000768
    CSI 4.98
    rCSI 12.63%
    PRS 90.9
  • kidney loop of Henle thin ascending limb epithelial cell CL1001107
    CSI 4.68
    rCSI 12.1%
    PRS 93
  • myeloid dendritic cell CL0000782
    CSI 4.62
    rCSI 6.69%
    PRS 98.76
  • choroid plexus epithelial cell CL0000706
    CSI 4.04
    rCSI 6.61%
    PRS 89.72
  • neutrophil CL0000775
    CSI 4
    rCSI 22.35%
    PRS 91.88
  • lung ciliated cell CL1000271
    CSI 3.65
    rCSI 4.22%
    PRS 90.53
  • centrilobular region hepatocyte CL0019029
    CSI 3.41
    rCSI 8.9%
    PRS 90.84
  • mature NK T cell CL0000814
    CSI 3.35
    rCSI 4.29%
    PRS 96.6
  • periportal region hepatocyte CL0019026
    CSI 3.15
    rCSI 12.23%
    PRS 91.38
  • inflammatory macrophage CL0000863
    CSI 2.81
    rCSI 4.81%
    PRS 98.97
  • multi-ciliated epithelial cell CL0005012
    CSI 2.65
    rCSI 2.64%
    PRS 90.07
  • hepatocyte CL0000182
    CSI 2.61
    rCSI 4.66%
    PRS 93.05
  • ciliated epithelial cell CL0000067
    CSI 2.46
    rCSI 2.17%
    PRS 87.91
  • professional antigen presenting cell CL0000145
    CSI 2.41
    rCSI 8.29%
    PRS 95.94
  • tissue-resident macrophage CL0000864
    CSI 2.25
    rCSI 10.51%
    PRS 98.43
  • metallothionein-positive alveolar macrophage CL4033042
    CSI 2.06
    rCSI 22.44%
    PRS 97.9
  • ciliated columnar cell of tracheobronchial tree CL0002145
    CSI 2.06
    rCSI 4.69%
    PRS 88.65
  • intestinal tuft cell CL0019032
    CSI 1.6
    rCSI 2.44%
    PRS 95.32
  • dendritic cell, human CL0001056
    CSI 1.56
    rCSI 2.39%
    PRS 97.76

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [C5AR1](/details-gene/728), or Complement C5a Receptor 1, encodes a G protein-coupled receptor that is the primary binding site for the potent pro-inflammatory anaphylatoxin, C5a. This receptor is a critical component of the innate immune system, mediating the chemotactic and activating effects of the complement cascade. **Overall**, its expression is highest in cells of the myeloid lineage, particularly monocytes and macrophages, positioning it as a key sensor for inflammatory signals and a mediator of cellular recruitment to sites of injury or infection. Its function is central to processes such as the '[inflammatory response](/details-go/GO:0006954)' and '[neutrophil chemotaxis](/details-go/GO:0030593)', and dysregulation of its signaling is implicated in a variety of inflammatory and autoimmune diseases. ## Cellular Roles and Expression Landscape The expression profile of [C5AR1](/details-gene/728) firmly establishes its role as a cornerstone of the mononuclear phagocyte system. The gene shows the highest significance in various monocyte subsets, including '[CD14-low, CD16-positive monocyte](/details-cell/CL0002396)' (CSI: 43.32) and '[CD14-positive, CD16-positive monocyte](/details-cell/CL0002397)' (CSI: 19.53), suggesting it is a defining marker for these circulating innate immune cells. This pattern extends to tissue-resident and elicited macrophages, where [C5AR1](/details-gene/728) also demonstrates high significance. It is prominently expressed in '[elicited macrophage](/details-cell/CL0000861)' (CSI: 19.14), '[Kupffer cell](/details-cell/CL0000091)' in the liver (CSI: 9.05), '[colon macrophage](/details-cell/CL0009038)' (CSI: 8.01), and placental '[Hofbauer cell](/details-cell/CL3000001)' (CSI: 7.61). This broad expression across diverse macrophage populations highlights its fundamental role in sensing complement activation and initiating local immune responses within different organ systems. The receptor's presence on '[CD1c-positive myeloid dendritic cell](/details-cell/CL0002399)' (CSI: 8.94) further indicates a function in bridging innate sensing with the activation of adaptive immunity. Interestingly, notable expression is also observed in non-immune cells such as '[ependymal cell](/details-cell/CL0000065)' (CSI: 14.68) and '[cardiac muscle cell](/details-cell/CL0000746)' (CSI: 7.39). This suggests that [C5AR1](/details-gene/728) may have specialized, non-canonical roles in the central nervous system and cardiac tissue, potentially related to inflammation, injury response, or tissue homeostasis. The highly specific expression pattern, primarily restricted to myeloid and select other cell types, underscores its specialized function in mediating C5a-driven biological processes. ## Pathways and Molecular Function Functionally, [C5AR1](/details-gene/728) operates as a '[complement component c5a receptor activity](/details-go/GO:0004878)' within the broader family of '[G protein-coupled receptor activity](/details-go/GO:0004930)'. Its activation by C5a initiates a cascade of intracellular events primarily through '[G alpha (i) signalling events](/details-pathway/R-HSA-418594)', as annotated in Reactome. This signaling is integral to the '[complement cascade](/details-pathway/R-HSA-166658)' and is a key driver of the '[innate immune system](/details-pathway/R-HSA-168249)'. The downstream consequences of [C5AR1](/details-gene/728) activation are pleiotropic and profoundly pro-inflammatory. Gene Ontology terms highlight its role in orchestrating cell migration, including '[chemotaxis](/details-go/GO:0006935)', '[positive regulation of macrophage chemotaxis](/details-go/GO:0010759)', and specifically '[neutrophil chemotaxis](/details-go/GO:0030593)'. Consistent with its role in myeloid cell function, it is also involved in '[neutrophil degranulation](/details-pathway/R-HSA-6798695)' and '[microglial cell activation](/details-go/GO:0001774)'. Furthermore, signaling through [C5AR1](/details-gene/728) leads to a '[positive regulation of cytosolic calcium ion concentration](/details-go/GO:0007204)' and the activation of the '[positive regulation of erk1 and erk2 cascade](/details-go/GO:0070374)', linking inflammatory sensing to cell activation and proliferation. These molecular functions align perfectly with its high expression in monocytes and macrophages, which rely on these pathways to migrate to inflammatory sites and execute effector functions. ## Research Directions The well-established role of the C5a-[C5AR1](/details-gene/728) axis in inflammation, combined with its specific expression pattern, presents several avenues for future research. The receptor's function in non-myeloid cells, such as ependymal cells, remains particularly intriguing and underexplored. **Proposed Hypotheses:** 1. **Role in Neuroinflammation:** The significant expression of [C5AR1](/details-gene/728) in '[ependymal cell](/details-cell/CL0000065)' suggests a direct role in central nervous system immunology. We hypothesize that C5a produced during systemic inflammation or local CNS injury activates [C5AR1](/details-gene/728) on ependymal cells, leading to altered cerebrospinal fluid dynamics, breakdown of the blood-CSF barrier, and subsequent recruitment of peripheral immune cells into the CNS, thereby exacerbating neuroinflammatory conditions. 2. **Modulation of Tissue-Specific Macrophage Phenotypes:** Given its expression across diverse tissue-resident macrophages (e.g., Kupffer, colon), we hypothesize that [C5AR1](/details-gene/728) signaling is context-dependent, differentially shaping macrophage polarization and function based on the specific tissue microenvironment. For instance, in the liver, C5a-[C5AR1](/details-gene/728) signaling in '[Kupffer cell](/details-cell/CL0000091)' may primarily drive pro-inflammatory responses, whereas in the placenta, its activation on '[Hofbauer cell](/details-cell/CL3000001)' could be involved in regulating tolerance or vascular remodeling. **Experimental Approach:** To test the first hypothesis regarding neuroinflammation, a conditional knockout mouse model could be generated to specifically delete *C5ar1* in ependymal cells (e.g., using a Foxj1-Cre driver line). Following induction of a systemic inflammatory challenge (e.g., intraperitoneal LPS injection) or a model of sterile brain injury, several readouts could be assessed. These would include measuring inflammatory cytokine levels (e.g., IL-6, TNF-alpha) in the cerebrospinal fluid, quantifying immune cell infiltration into the brain parenchyma via flow cytometry and immunohistochemistry, and assessing blood-CSF barrier integrity using fluorescent tracers. A significant reduction in these neuroinflammatory markers in the conditional knockout mice compared to wild-type controls would support the hypothesis that ependymal [C5AR1](/details-gene/728) is a critical gateway for CNS inflammation. **Therapeutic Potential:** [C5AR1](/details-gene/728) is an exceptionally attractive therapeutic target for a wide range of inflammatory and autoimmune disorders, including rheumatoid arthritis, sepsis, and lupus. As a cell surface G protein-coupled receptor, it is highly druggable by small molecule antagonists or therapeutic antibodies. The therapeutic strategy would focus on **inhibition** of the receptor to block the potent chemotactic and pro-inflammatory effects of C5a. By preventing the recruitment and activation of neutrophils, monocytes, and macrophages to sites of inflammation, [C5AR1](/details-gene/728) antagonists could effectively dampen excessive immune responses and mitigate tissue damage. Several such inhibitors are already in clinical development, validating the potential of this approach.

Genular Protein ID: 1667935445

Symbol: C5AR1_HUMAN

Name: C5a anaphylatoxin chemotactic receptor 1

UniProtKB Accession Codes:

P21730

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 1 DrugCentral 1 EMBL 9 EMDB 11 Ensembl 1 EvolutionaryTrace 1 ExpressionAtlas 1 GO 32 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 15 PDBsum 15 PIR 1 PRINTS 3 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 4 RefSeq 1 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 2007135

Title: Expression cloning of a receptor for C5a anaphylatoxin on differentiated HL-60 cells.

PubMed ID: 2007135

DOI: 10.1021/bi00226a002

PubMed ID: 1847994

Title: The chemotactic receptor for human C5a anaphylatoxin.

PubMed ID: 1847994

DOI: 10.1038/349614a0

PubMed ID: 15057824

Title: The DNA sequence and biology of human chromosome 19.

PubMed ID: 15057824

DOI: 10.1038/nature02399

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 8383526

Title: Human chemotaxis receptor genes cluster at 19q13.3-13.4. Characterization of the human C5a receptor gene.

PubMed ID: 8383526

DOI: 10.1021/bi00056a007

PubMed ID: 8182049

Title: The amino terminus of the human C5a receptor is required for high affinity C5a binding and for receptor activation by C5a but not C5a analogs.

PubMed ID: 8182049

DOI: 10.1016/s0021-9258(17)36643-7

PubMed ID: 7622471

Title: Mutation of glutamate 199 of the human C5a receptor defines a binding site for ligand distinct from the receptor N terminus.

PubMed ID: 7622471

DOI: 10.1074/jbc.270.28.16625

PubMed ID: 7642584

Title: Identification of the major phosphorylation sites in human C5a anaphylatoxin receptor in vivo.

PubMed ID: 7642584

DOI: 10.1074/jbc.270.32.19166

PubMed ID: 9553099

Title: Residues 21-30 within the extracellular N-terminal region of the C5a receptor represent a binding domain for the C5a anaphylatoxin.

PubMed ID: 9553099

DOI: 10.1074/jbc.273.17.10411

PubMed ID: 10636859

Title: Human complement 5a (C5a) anaphylatoxin receptor (CD88) phosphorylation sites and their specific role in receptor phosphorylation and attenuation of G protein-mediated responses. Desensitization of C5a receptor controls superoxide production but not receptor sequestration in HL-60 cells.

PubMed ID: 10636859

DOI: 10.1074/jbc.275.3.1656

PubMed ID: 11342590

Title: Sulfated tyrosines contribute to the formation of the c5a docking site of the human c5a anaphylatoxin receptor.

PubMed ID: 11342590

DOI: 10.1084/jem.193.9.1059

PubMed ID: 12464600

Title: Phosphorylation of key serine residues is required for internalization of the complement 5a (C5a) anaphylatoxin receptor via a beta-arrestin, dynamin, and clathrin-dependent pathway.

PubMed ID: 12464600

DOI: 10.1074/jbc.m210120200

PubMed ID: 12835319

Title: C5a receptor oligomerization. I. Disulfide trapping reveals oligomers and potential contact surfaces in a G protein-coupled receptor.

PubMed ID: 12835319

DOI: 10.1074/jbc.m305606200

PubMed ID: 15153520

Title: Chemotaxis inhibitory protein of Staphylococcus aureus binds specifically to the C5a and formylated peptide receptor.

PubMed ID: 15153520

DOI: 10.4049/jimmunol.172.11.6994

PubMed ID: 15542591

Title: Residues 10-18 within the C5a receptor N terminus compose a binding domain for chemotaxis inhibitory protein of Staphylococcus aureus.

PubMed ID: 15542591

DOI: 10.1074/jbc.m412230200

PubMed ID: 21706042

Title: Tyrosine sulfation in N-terminal domain of human C5a receptor is necessary for binding of chemotaxis inhibitory protein of Staphylococcus aureus.

PubMed ID: 21706042

DOI: 10.1038/aps.2011.53

PubMed ID: 29300009

Title: Structure of the complement C5a receptor bound to the extra-helical antagonist NDT9513727.

PubMed ID: 29300009

DOI: 10.1038/nature25025

Sequence Information:

  • Length: 350
  • Mass: 39336
  • Checksum: 9334BB39A2C96D3D
  • Sequence:
    • MDSFNYTTPD YGHYDDKDTL DLNTPVDKTS NTLRVPDILA LVIFAVVFLV GVLGNALVVW 
VTAFEAKRTI NAIWFLNLAV ADFLSCLALP ILFTSIVQHH HWPFGGAACS ILPSLILLNM 
YASILLLATI SADRFLLVFK PIWCQNFRGA GLAWIACAVA WGLALLLTIP SFLYRVVREE 
YFPPKVLCGV DYSHDKRRER AVAIVRLVLG FLWPLLTLTI CYTFILLRTW SRRATRSTKT 
LKVVVAVVAS FFIFWLPYQV TGIMMSFLEP SSPTFLLLKK LDSLCVSFAY INCCINPIIY 
VVAGQGFQGR LRKSLPSLLR NVLTEESVVR ESKSFTRSTV DTMAQKTQAV