Sustained signaling by phospholipase C-gamma mediates nerve growth factor-triggered gene expression

In contrast to conventional signaling by growth factors that requires their continual presence, a 1-min pulse of nerve growth factor (NGF) is sufficie nt to induce electrical excitability in PC12 cells due to induction of the peripheral nerve type 1 (PN1) sodium channel gene. We have investigated the mechanism for this triggered signaling pathway by NGF in PC12 cells. Mutat ion of TrkA at key autophosphorylation sites indicates an essential role fo r the phospholipase C-gamma (PLC-gamma) binding site, but not the Shc bindi ng site, for NGF-triggered induction of PN1, In concordance with results wi th Trk mutants, drug-mediated inhibition of PLC-gamma activity also blocks PN1 induction by NGF, Examination of the kinetics of TrkA autophosphorylati on indicates that triggered signaling does not result from sustained activa tion and autophosphorylation of the TrkA receptor kinase, whose phosphoryla tion state declines rapidly after NGF removal. Rather, TrkA triggers an une xpectedly prolonged phosphorylation and activation of PLC-gamma signaling t hat is sustained for up to 2 h, Prevention of the elevation of intracellula r Ca2+ levels using BAPTA-AM results in a block of PN1 induction by NGF. Su stained signaling by PLC-gamma provides a means for differential neuronal g ene induction after transient exposure to NGF.