The common neurotrophin receptor p75NTR enhances the ability of PC12 cells to resist oxidative stress by a trkA-dependent mechanism

Functional role(s) for the common neurotrophin receptor p75(NTR) in nerve growth factor (NGF) signaling have yet to be fully elucidated. Many studies have demonstrated that p75(NTR) can enhance nerve growth factor-induced survival mediated via the trkA receptor. In addition, newly identified pathways for p75(NTR) signaling have included distinct p75(NTR)-specific and trk-independent effects which generally appear to be pro-apoptotic. In the present study, we have examined the influence of p75(NTR) on NGF-mediated protective effects from hydrogen peroxide (H2O2)-induced apoptotic cell death of PC12 cells. Exposure of PC12 cells to H2O2 resulted in Caspase-3 activation and apoptosis. NGF protected PC12 cells against H2O2-mediated apoptosis in a dose-dependent manner and inhibited Caspase-3 activation. These effects of NGF required activation of both PI 3-kinase and MAP kinase signal pathways. Where NGF binding to p75(NTR) was blocked by treating cells with either BDNF or PD90780, and where p75(NTR) expression was reduced by treating cells with antisense oligonucleotide to p75(NTR), the protective effects of NGF were attenuated. Further, NGF had no effect on cell viability in PC12(nnr5) cells, which express only p75(NTR). When trkA-mediated signal transduction was blocked, leaving p75(NTR) signaling activated, PC12 cells were not more vulnerable to H2O2. These data suggest that p75(NTR) enhances the ability of PC12 cells to resist oxidative stress by a trkA-dependent mechanism, potentially by allosteric mechanisms. Further, potential trkA-independent and pro-apoptotic signaling of p75(NTR) does not contribute to apoptotic cell death of PC12 cells in a setting of oxidative insult.