PRJNA577963
Transcriptome-wide identification of gene targets by blocking L-type voltage-gated calcium channels in microglial cells
Anti-inflammatory drugs targeting microglia activation for the treatment of neurodegenerative diseases are very limited. We recently identified novel small inhibitors that effectively block L-type voltage-gated calcium channels (L-VGCC), and prevent microglia activation and infiltration, as well as associated complications (angiogenesis). RNA-seq was used to profile the transcritome-wide gene targets of the most effective L-VGCC blocker (Zinc20167861) in BV2 microglia cells. The transcriptome analysis revealed that LPS treatment significantly up-regulated the expression of 1281 genes when compared to PBS-treated control. The functional gene enrichment analysis revealed that numerous genes involved in TNF signaling pathway (16 genes), cytokine-cytokine receptor interaction pathway (22 genes), chemokine signaling pathway (17 genes) IL-17 signaling pathway (15 genes) and specific reactive microgila marker genes (10 genes). Significantly down-regulated the pro-inflammatory pathway genes by the Zinc20167861 compound along with specific reactive microgila marker genes such as CFB, CSF3, CSF2, GBP3, JAK2, STAT5A, TLR2, TNF, TNFSF15 and SLCO2B1 respectively. In addition to that calcium channel blockers significantly down-regulated the various pathways like wnt signaling pathway (12 genes), angiotensin II-stimulated signaling through G proteins and beta-arrestin (4 genes), heterotrimeric G-protein signaling pathway-rod outer segment phototransduction (3 genes), and the p53 pathway (5 genes). The inhibitor Zinc20167861 more robustly downregulated the following pathway genes than amlodipine: Wnt signaling pathway (12 genes), angiotensin II-stimulated signaling through G proteins and beta-arrestin (4 genes), the p53 pathway (5 genes) and the PDGF signaling pathway (8 genes). Our findings suggest that calcium channel blockers inhibits multiple pro-inflammatory signaling pathway genes and specificly reactive microgila marker genes. Its represents a new strategy to prevent inflammation related to microglia activation.