Uncovering malathion (an organophosphate insecticide) action on Ca signal transduction and investigating the effects of BAPTA-AM (a cell-permeant Ca chelator) on protective responses in glial cells.

Malathion, one of commonly used organophosphate insecticides, has a wide range of toxic actions in different models. However, the effect of this compound on Ca homeostasis and its related cytotoxicity in glial cells is elusive. This study examined whether malathion evoked intracellular Ca concentration ([Ca]) rises and established the relationship between Ca signaling and cytotoxicity in normal human astrocytes, rat astrocytes and human glioblastoma cells. The data show that malathion induced concentration-dependent [Ca] rises in Gibco Human Astrocytes (GHA cells), but not in DI TNC1 normal rat astrocytes and DBTRG-05MG human glioblastoma cells. In GHA cells, this Ca signal response was reduced by removing extracellular Ca. In Ca-free medium, pretreatment with the endoplasmic reticulum Ca pump inhibitor thapsigargin abolished malathion-induced [Ca] rises. Conversely, incubation with malathion abolished thapsigargin-induced [Ca] rises. Inhibition of phospholipase C (PLC) with U73122 also blocked malathion-induced [Ca] rises. In Ca-containing medium, malathion-induced [Ca] rises was inhibited by store-operated Ca channel blockers (2-APB, econazole or SKF96365) and the protein kinase C (PKC) inhibitor GF109203X. Malathion (5-25 μM) concentration-dependently caused cytotoxicity in GHA, DI TNC1 and DBTRG-05MG cells. This cytotoxic effect was partially prevented by prechelating cytosolic Ca with BAPTA-AM (a selective Ca chelator) only in GHA cells. Together, in GHA but not in DI TNC1 and DBTRG-05MG cells, malathion induced [Ca] rises by inducing PLC-dependent Ca release from the endoplasmic reticulum and Ca entry via PKC-sensitive store-operated Ca channels. Furthermore, malathion induced Ca-associated cytotoxicity, suggesting that Ca chelating may have a protective effect on malathion-induced cytotoxicity in normal human astrocytes.