Neurotrophin-induced upregulation of p75NTR via a protein kinase C-delta-dependent mechanism

Abstract

Neurotrophins exert their biological effects via p75NTR and Trk receptors. Functional interplay between these two receptors has been widely explored with respect to p75NTR enhancing the activation and signalling of Trk, but few studies address the bidirectional aspects. We have previously demonstrated that the expression of p75NTR can be differentially modulated by different Trk receptor mutations. Here we investigate the mechanism of Nerve Growth Factor (NGF)-induced upregulation of p75NTR expression. We utilize pharmacological inhibition to investigate the role of various TrkA-associated signalling intermediates in this regulatory cascade. Notably, the inhibition of phospholipase C-gamma (PLC-gamma) using U73122, prevented the NGF-induced upregulation of p75NTR protein and mRNA. The inhibition of protein kinase C-delta (PKC-delta) activation by rottlerin, a selective PKC-delta inhibitor, and by small interfering RNA (siRNA) directed against PKC-delta also inhibited this NGF-induced upregulation. Finally, we also show that in cerebellar granule neurons, BDNF acting via TrkB increases p75NTR expression in a PKC-delta dependent manner. These results indicate the importance of Trk-dependent PLC-gamma and PKC-delta activation for downstream regulation of p75NTR protein expression in response to neurotrophin stimulation, a process that has implications to the survival and growth of the developing nervous system.