Intracellular Calcium Plays a Critical Role in the Microcystin-LR-Elicited Neurotoxicity Through PLC/IP3 Pathway

Neurotoxicity of microcystin-leucine-arginine (MCLR) has been widely reported. However, the mechanism is not fully understood. Using primary hippocampal neurons, we tested the hypothesis that MCLR-triggered activation in intracellular free calcium concentration ([Ca2+](i)) induces the death of neurons. Microcystin-leucine-arginine inhibited cell viability at a range of 0.1 to 30 mol/L and caused a dose-dependent increase in [Ca2+](i). This increase in [Ca2+](i) was observed in Ca2+-free media and blocked by an endoplasmic reticulum Ca2+ pump inhibitor, suggesting intracellular Ca2+ release. Moreover, pretreatment of hippocampal neurons with intracellular Ca2+ chelator (O,O-bis (2-aminophenyl) ethyleneglycol-N,N,N,N-tetraacetic acid, tetraacetoxy-methyl ester) and inositol 1,4,5-trisphosphate receptor antagonist (2-aminoethoxydiphenyl borate) could block both the Ca2+ mobilization and the neuronal death following MCLR exposure. In contrast, the ryanodine receptor inhibitor (dantrolene) did not ameliorate the effect of MCLR. In conclusion, MCLR disrupts [Ca2+](i) homeostasis in neurons by releasing Ca2+ from intracellular stores, and this increase in [Ca2+](i) may be a key determinant in the mechanism underlying MCLR-induced neurotoxicity.