A comparative review on TLQP-21 receptors: rodent versus human

Growing functional information regarding bioactive TLQP-21 has led to the ubiquitous demand for identification of receptors associated to the peptide, which resulted in the first wave of murine TLQP-21 receptors, gC1qR and C3AR1. gC1qR was identified as receptor of TLQP-21 using chemical crosslinking and monomeric avidin column purification following by MS analysis. TLQP-21 responsive CHO-K1 cells were used to search for its receptor, C3AR1. Putative GPCRs, which may partake in regulating intracellular biological functions induced by TLQP-21, were indexed after the CHO-K1 cellular transcriptome was sequenced using unbiased Genome Wide Sequencing. TLQP-21 binding in the cells were found to be reduced by the gene knockdown with the siRNAs targeting C3AR1. C3AR1 antagonist, SB290157 was shown to prohibit TLQP-21 activity in CHOK1 cells. But this finding was not demonstrable in human cell line. The differences of human TLQP-21 sequence with that of murine TLQP-21 explains the poor binding of the human orthologue with its corresponding receptor. This may suggest a different set of receptors when considering human and rodent variants of TLQP-21. The identification of HSPA8 as receptor was performed using affinity based chromatography and mass spectrometry from human SHSY-5Y cells. Molecular studies in silico revealed that the peptide binding pocket in HSPA8 is an appropriate fit for TLQP-21 docking. Cross-linking and FACS methods presented the TLQP-21 binding to cells from the SHSY-5Y line. The establishment of HSPA8 as a putative receptor for human TLQP-21 can be exploited to explore new horizon in diagnosis and therapies for VGF related human diseases.