Disease relevance of C5r1

• Experimental diffuse axonal injury induces enhanced neuronal C5a receptor mRNA expression in rats [1].
• A new small molecule C5a receptor antagonist inhibits the reverse-passive Arthus reaction and endotoxic shock in rats [2].
• A small molecule C5a receptor antagonist protects kidneys from ischemia/reperfusion injury in rats [3].
• Characterisation of C5a receptor agonists from phage display libraries [4].
• In this study, we investigated the expression of the C5aR in spinal cords of Lewis rats with experimental allergic encephalomyelitis (EAE) [5].

Psychiatry related information on C5r1

• In this study we used orally active C5a receptor antagonists (PMX53 and PMX205) developed in our laboratories in a rat model of 3-nitropropionic acid (3-NP) -induced Huntington's disease [6].
• Complement C5a receptor-mediated signaling may be involved in neurodegeneration in Alzheimer's disease [7].

High impact information on C5r1

• RESULTS: In vivo treatment of rats with LPS induced C5a receptor mRNA and protein in hepatocytes with a maximum after 8-10 hours [8].
• Lipopolysaccharide (LPS) has been reported to enhance C5a receptor expression in murine livers [8].
• Expression of C3aR and C5aR mRNAs and proteins was also observed in vitro in cultured cerebellar granule cells [9].
• Our results provide the first evidence that C3aR and C5aR are both expressed in cerebellar granule cells during development and that C5a, but not C3a, is a potent inhibitor of apoptotic cell death in cultured granule neurons [9].
• The neuroprotective effect of the C5aR agonist was associated with a marked inhibition of caspase-9 activity and partial restoration of mitochondrial integrity [9].

Biological context of C5r1

• We found that, in cultured granule neurons in which apoptosis was induced by serum deprivation and low potassium concentration, a C5aR agonist promoted cell survival and inhibited caspase-3 activation and DNA fragmentation [9].
• Analysis of the tissue distribution of the rat C5a receptor and inhibition of C5a-mediated effects through the use of two MoAbs [10].
• Pretreatment with sCR1 or C5aRA suppressed the up-regulation of C5aR expression as well as cytokine messages in the lungs [11].
• We used a hybridization probe produced by PCR utilizing degenerate primers which corresponded to conserved parts of the human, canine and murine C5a receptor nucleotide sequences and to the published partial amino acid sequence of the rat C5a receptor to screen a rat macrophage cDNA library [12].
• We tested the hypothesis that agonist-induced desensitization involves C3aR and C5aR phosphorylation by G protein-coupled receptor kinases (GRK) [13].

Anatomical context of C5r1

• A cDNA clone, DTJP03, encoding an orphan receptor, was isolated from a canine thyroid library, and found to exhibit 68.6% amino-acid identity with the recently described human C5a receptor [14].
• Binding studies performed on membranes from COS-7 cells expressing the recombinant receptor demonstrated that DTJP03 encoded a high-affinity C5a receptor, with a Kd of 1.2 nM [14].
• In order to corroborate this mechanism, the distribution of anaphylatoxin receptors in the different cell types of rat liver was determined by quantitative RT-PCR with primers specific for the rat C5a receptor (rC5aR) using RNA isolated from KC, sinusoidal endothelial cells (SEC), hepatic stellate cells (HSC) and HC [15].
• Expression of a functional C5a receptor in regenerating hepatocytes and its involvement in a proliferative signaling pathway in rat [16].
• Expression and function of the C5a receptor in rat alveolar epithelial cells [17].

Associations of C5r1 with chemical compounds

• Extracellular EGTA partially prevented this response, suggesting that activation of the C5a receptor promotes both the release of calcium from intracellular stores, and the influx of extracellular calcium [14].
• Intracellular free calcium concentrations were measured by Quin-2 fluorescence assays in Chinese hamster ovary cells stably transfected with the canine C5a receptor [14].
• C5aR was usually expressed at the site of exposure to pathogens, such as in salivary gland or lung, and was up-regulated in liver in the inflammatory state induced by lipopolysaccharide (LPS) administration [18].
• Through a high capacity screening followed by chemical optimization, we identified a novel non-peptide C5a receptor antagonist, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-1- carboxamide hydrochloride (W-54011) [19].

Physical interactions of C5r1

• However, little is known about the role of the C5a/C5aR complex in liver and its involvement during a proliferative process [16].

Regulatory relationships of C5r1

• Interleukin-6 (IL-6) as a main inflammatory mediator in the liver induced a de novo expression of functional C5aR in HC in-vitro and in-vivo [20].
• Based on these data, IFN-gamma that induces monocyte maturation as reflected by increased Ia expression conversely inhibits C5a receptor expression [21].

Other interactions of C5r1

• Here, we show that transient expression of C3aR and C5aR occurs in cerebellar granule neurons in vivo with a maximal density in 12-day-old rat, suggesting a role of these receptors during development of the cerebellum [9].
• In contrast, LPS failed to induce C5aR directly in cultured HC in-vitro but induced C5aR in HC in vivo and in co-cultures of HC and KC which release IL-6 upon stimulation with LPS [20].
• These data suggest that complement-mediated inflammation can be modulated at the C5a receptor level, independent of proinflammatory TNF-alpha production, and prevent acute local and remote organ injury [22].

Analytical, diagnostic and therapeutic context of C5r1

• Quantification of the mRNAs by real-time reverse transcription-PCR showed a peak of expression at day 2 in vitro (DIV 2); the C3aR and C5aR proteins were detected by Western blot analysis at DIV 4 and by flow cytometry and immunocytochemistry in differentiating neurons with a maximum density at DIV 4-9 [9].
• Genes encoding C5a-receptor subtypes were subsequently searched for by PCR in genomic DNA from human, canine, rat and bovine sources [14].
• We have evaluated the expression of C5aR in regenerating rat hepatocytes following a partial hepatectomy and in hepatocyte cultures [16].
• Since the intrathecal generation of anaphylatoxin C5a has been shown to mediate inflammatory effects within the central nervous system, we sought to characterize the cellular expression of the mRNA for the C5a receptor (C5aR, CD88) in brains of rats with experimental diffuse axonal injury (DAI) by in situ hybridization [1].
• Molecular cloning and expression of the functional rat C5a receptor [12].

References