Neurotrophins (NTs) play an essential role in modulating activity-dependent neuronal plasticity. In this context, the site and extent of NT secretion are of crucial importance. Here, we demonstrate that the activation of phospolipase C (PLC) and the subsequent mobilization of Ca(2+) from intracellular stores are essential for NT secretion initiated by both Trk and glutamate receptor activation. Mutational analysis of tyrosine residues, highly conserved in the cytoplasmic domain of all Trk receptors, revealed that the activation of PLC-gamma in cultured hippocampal neurons and nnr5 cells is necessary to mobilize Ca(2+) from intracellular stores, the key mechanism for regulated NT secretion. A similar signalling mechanism has been identified for glutamate-mediated NT secretion-which in part depends on the activation of PLC via metabotropic receptors-leading to the mobilization of Ca(2+) from internal stores by inositol trisphosphate. Thus, PLC-mediated signal transduction pathways are the common mechanisms for both Trk- and mGluRI-mediated NT secretion.