title: The role of calcineurin signaling in microcystin-LR triggered neuronal toxicity.
abstract: Microcystin-LR (MCLR) is a commonly acting potent hepatotoxin and has been pointed out of potentially causing neurotoxicity, but the exact mechanisms of action still remain unclear. Using proteomic analysis, forty-five proteins were identified to be significantly altered in hippocampal neurons of rats treated with MCLR. Among them, Ca(2+)-activated phosphatase calcineurin (CaN) and the nuclear factor of activated T-cells isoform c3 (NFATc3) were up-regulated remarkably. Validation of the changes in CaN and NFATc3 expression by Western blotting demonstrated CaN cleavage and subsequent NFATc3 nuclear translocation were generated, suggesting that exposure to MCLR leads to activation of CaN, which in turn activates NFATc3. Activation of CaN signaling has been reported to result in apoptosis via dephosphorylation of the proapoptotic Bcl-2 family member Bad. In agreement with this, our results revealed that treatment of neurons with the CaN inhibitor FK506 blocked the reduction in Bad dephosphorylation and cytochrome c (cyt c) release triggered by MCLR. Consistent with these biochemical results, we observed a marked decrease in apoptotic and necrotic cell death after MCLR exposure in the presence of FK506, supporting the hypothesis that MCLR appeared to cause neuronal toxicity by activation of CaN and the CaN-mediated mitochondrial apoptotic pathway.
authors.affiliation: College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Li
authors.affiliation: Institute of Agricultural Quality Standards &Testing Technology, Hubei Academy of Agricultural Sciences, Wuhan 430064, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.affiliation: College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Dang
authors.affiliation: College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Liu
authors.affiliation: College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Jianghua
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D008387:Marine Toxins; D052998:Microcystins / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D008387:Marine Toxins; D052998:Microcystins; D019703:Calcineurin; C057862:cyanoginosin LR