TRIMETHYLTIN STIMULATES PROTEIN-KINASE-C TRANSLOCATION THROUGH RECEPTOR-MEDIATED PHOSPHOLIPASE-C ACTIVATION IN PC12 CELLS

Trimethyltin (TMT) is a potent neurotoxic compound that initiates a de layed neuronal cell death. Previously we have shown that TMT-induced c ytotoxicity is associated with protein kinase C (PKC) translocation an d activation. The present study investigates the mechanism underlying TMT-stimulated PKC translocation in PC12 cells. TMT exposure led to a rapid increase in intracellular levels of inositol 1,4,5-trisphosphate (IP3), a product of phospholipase C (PLC). This was significantly dec reased by pretreating cells with antagonists to either the cholinergic muscarinic receptor (atropine) or the glutamatergic metabotropic rece ptor [(+)-alpha-methyl-4-carboxyphenylglycine; (+)-MCPG]. Furthermore, the rise in IP3 level was blocked by pretreating cells with a PLC inh ibitor (U-73122) or by a combination of atropine and (+)-MCPG, This pr etreatment also significantly decreased TMT-stimulated PKC translocati on, indicating that TMT-mediated PKC translocation was related to PLC activation, presumably through formation of diacylglycerol, an endogen ous activator of PKC and product of PLC. It is interesting that atropi ne and (+)-MCPG did not provide protection against TMT-induced cytotox icity in these cells. However, these data suggest that TMT causes the release of cellular constituents that activate G protein-coupled recep tors, ultimately leading to PKC translocation.