Trimethyltin Stimulates Protein Kinase C Translocation Through Receptor‐Mediated Phospholipase C Activation in PC12 Cells

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Abstract
Trimethyltin (TMT) is a potent neurotoxic compound that initiates a delayed neuronal cell death. Previously we have shown that TMT‐induced cytotoxicity is associated with protein kinase C (PKC) translocation and 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 decreased by pretreating cells with antagonists to either the cholinergic muscarinic receptor (atropine) or the glutamatergic metabotropic receptor [(+)‐α‐methyl‐4‐carboxyphenylglycine; (+)‐MCPG]. Furthermore, the rise in IP3 level was blocked by pretreating cells with a PLC inhibitor (U‐73122) or by a combination of atropine and (+)‐MCPG. This pretreatment also significantly decreased TMT‐stimulated PKC translocation, indicating that TMT‐mediated PKC translocation was related to PLC activation, presumably through formation of diacylglycerol, an endogenous activator of PKC and product of PLC. It is interesting that atropine and (+)‐MCPG did not provide protection against TMT‐induced cytotoxicity in these cells. However, these data suggest that TMT causes the release of cellular constituents that activate G protein‐coupled receptors, ultimately leading to PKC translocation.

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