Disease relevance of GPR77

• However, ligation of C5L2 by anaphylatoxin did potentiate the degranulation response to cross-linkage of the high affinity IgE receptor by a pertussis toxin-sensitive mechanism [1].
• Similarly, PMN from patients with progressive sepsis showed significantly reduced C5L2 expression (n = 26), which was virtually abolished in patients who developed multiorgan failure (n = 10) [2].
• CONCLUSIONS: The S323I variant may alter C5L2 function and might be one molecular basis contributing to familial combined hyperlipidemia [3].

High impact information on GPR77

• In contrast, epithelial HeLa cells are found to constitutively express C5L2 but not the C5a receptor [4].
• Taken together, C5L2 is not a receptor for C3a or C3a-des-Arg(77) [4].
• In HeLa cells, interferon-gamma and TNF-alpha drastically reduce C5L2 expression [4].
• No C5a-dependent Ca(2+) signaling is observed even in these cells endogenously expressing C5L2 [4].
• C5L2 expression and its regulation are investigated on various cell lines by a novel C5L2-restricted binding assay and quantitative real time PCR [4].

Biological context of GPR77

• C5L2 down-regulation and decreased ASP response correlate (r = 0.761, p < 0.0001 for HSF and r = 0.451, p < 0.05 for 3T3-L1) [5].
• Stable transfection of human C5L2 cDNA into HEK293 cells results in ASP stimulation of triglyceride synthesis (TGS) (193 +/- 33%, 5 microM ASP, p < 0.001, where basal = 100%) and glucose transport (168 +/- 21%, 10 microM ASP, p < 0.001) [5].
• C5L2, a nonsignaling C5A binding protein [6].
• Acylation stimulating protein (ASP; C3adesArg) stimulates triglyceride synthesis (TGS) and glucose transport in preadipocytes/adipocytes through C5L2, a G-protein-coupled receptor [7].

Anatomical context of GPR77

• Analysis of GPR77 mRNA expression revealed signals in the frontal cortex, hippocampus and hypothalamus with high transcript levels in the liver [8].
• Here we show that both cell types and human adipose tissue express C5L2 mRNA and that the human fibroblasts express C5L2 protein at the cell surface [9].
• In contrast, no C5L2 expression was found on human neutrophils [10].
• Both receptors are coexpressed on human monocytes and the human mast cell line HMC-1; however, C5L2 expression on monocytes is weaker as compared with HMC-1 cells and highly variable [10].
• In mice, C5L2 is expressed in all adipose tissues, at levels comparable with other tissues [5].

Associations of GPR77 with chemical compounds

• Thus C5L2, a promiscuous complement fragment-binding protein with a high affinity site that binds C3a des-Arg(77)/ASP, may mediate the acylation-stimulating properties of this peptide [9].
• Unlike CD88 and C3a receptor, C5L2 transfected into RBL-2H3 cells does not support degranulation or increases in intracellular [Ca(2+)] and is not rapidly internalized in response to ligand binding [1].
• This is the first demonstration that C5L2 is a functional receptor, mediating ASP triglyceride stimulation [5].
• Both human and murine C5L2 bear a leucine for arginine replacement at this site [6].

Other interactions of GPR77

• A search of the GenBank genomic sequence databases revealed three previously unrecognized intronless genes encoding the orphan GPCrs (oGPCRs) GPR62, GPR63 and GPR77, with respective amino acid lengths of 368, 419 and 337 [8].
• The chemoattractant receptor-like protein C5L2 binds the C3a des-Arg77/acylation-stimulating protein [9].

Analytical, diagnostic and therapeutic context of GPR77

• Here we use (125)I-ligand binding assays and flow cytometry with fluorescently labeled ligands to demonstrate that neither C3a nor C3a-des-Arg(77) binds to C5L2 [4].

References