Activation of Protein Kinase C by Trimethyltin: Relevance to Neurotoxicity

Abstract

The differentiated PC12 cell neuronal model was used to determine the effect of trimethyltin (TMT) on protein kinase C (PKC). Cells treated with 5–20 µM TMT showed a partial and sustained PKC translocation within 30 min and persisted over a 24‐h period. TMT treatment was accompanied by a low level of PKC down‐regulation over 24 h, which was small compared with that produced by phorbol esters. Confocal imaging of differentiated PC12 cells showed that PKC translocates to the plasma membrane and the translocation is blocked by the PKC inhibitor chelerythrine (1 µM). Phorbol myristate‐induced PKC down‐regulation or inhibition with chelerythrine provided protection against TMT‐induced cytotoxicity. It was concluded that TMT‐induced PKC translocation and activation contribute to the cytotoxicity of TMT in differentiated PC12 cells.

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

“…These data suggest that TMT-stimulated PKC translocation is linked to PLC activation, presumably owing to diacylglycerol (a PLC product), which is an endogenous activatorof PKC. It is interesting that the combination of atropine and (+ ) -MCPG did not provide protection against TMT-induced cytotoxicity in differentiated PC 12 cells (data not shown), yet PKC inhibition has been shown to be protective against TMT in this model (Pavlakovié et a)., 1995b). Note that TMTinduced cytotoxicity assays were performed at 48 h of TMT exposure (Pavlakovid et al,l995b), and similar assays carried out at 30 mm of TMT exposure revealed no significant cell death.…”

Biological activity studies on organotin(IV)n+ complexes and parent compounds

“…Organotin(IV) compounds have been shown to affect cell signalling: they activate protein kinase C [105] and increase free arachidonic acid through the activation of phospholipase A 2 [106].…”

Protein Kinase Cϵ Regulates Tumor Necrosis Factor-α-Induced Stannin Gene Expression

“…In either case, it is clear from our work and that of others (Harry et al, 2003) that TNF␣, although involved, is not a causal part of the TMT signaling cascade. Since PKC has been implicated as having a regulatory role in both TNF␣-initiated signaling events and TMT toxicity (Pavlakovic et al, 1995;Basu et al, 2002), the functional role of PKC in Snn gene expression is not surprising. Studies have demonstrated that PKC⑀ is involved in several cellular processes, including cellular proliferation (Akita, 2002;Soh and Weinstein, 2003), cell death (Comalada et al, 2003;Jung et al, 2004), and the immune response (Aksoy et al, 2004).…”

“…PKC is known to be vital for TMT cytotoxicity in some cell types and is activated in response to TNF␣ signaling in HUVECs (Pavlakovic et al, 1995;Basu et al, 2002). Based on these observations, we hypothesized that PKC might mediate TNF␣-induced Snn gene expression.…”