Characterization of the neuroprotective and toxic effects of alpha7 nicotinic receptor activation in PC12 cells

The alpha7 nicotinic receptor partial agonist DMXB protected differentiated PC12 cells from NGF+ serum deprivation over a concentration range (1-10 microM) that correlated with activation of protein kinase C. Increased toxicity was observed at a higher concentration of DMXB (30 microM) that did not elevate protein kinase C activity, but did increase tyrosine protein kinase activity. Neuroprotection was blocked with the protein kinase C-inhibitor bis-indolemaleimide, while toxicity was attenuated with the tyrosine protein kinase-antagonists herbimycin and genistein. The alpha7-selective antagonist methyllyconitine attenuated both the protective and toxic actions of DMXB, but in temporally distinct manners. Methyllyconitine (1 microM) attenuated toxicity when added 10 s before, but not 10 s after, 30 microM DMXB. In contrast, it blocked neuroprotection when added 10 min post-agonist addition. This temporal difference in receptor-activation that was necessary for protection vs. toxicity reflected the time courses for agonist-induced desensitization of the receptor expressed in Xenopus oocytes. These results indicate that alpha7 nicotinic receptors act through different intracellular transduction processes to protect or kill cells. Further, they suggest that the transduction processes may be differentially activated depending on the amplitude and duration of calcium signals.