Synaptotagmin IV (SytIV) is an immediate early gene induced by membrane depolarization in PC12 cells and in rat brain. However, little is known about the function of SytlV or the functional relationship between SytlV and SytI, because SytlV has yet to be localized. Here we show that SytlV was localized at the Golgi and distal part of neurites in nerve growth factor- differentiated PC12 cells and cultured hippocampal neurons by immunocytochemistry using an isoform-specific antibody (anti-SytIV). These SytlV signals were not colocalized well with SytI signals. Upon membrane depolarization, SytlV signals were increased at both the Golgi and distal part of neurites within several hours in both types of cells. We further show that the increase of SytlV protein levels results from protein kinase A- dependent gene up-regulation. In hippocampal neurons, SytlV was developmentally regulated. These results suggest that SytlV may play a role at the Golgi and tips of neurites during development and synaptic plasticity.