We examined effects of phorbol esters on the amount and the subcellular distribution of the activity-regulated protein Vesl-1S/ Homer-la in cultured hippocampal neurons. Major Vesl-1S immunoreactivity (IR) was detected throughout neuronal somata under control conditions. Bath application of phorbol esters, PMA and PDBU resulted in the increase in the amount of Vesl-1S proteins and promoted punctate distribution of Vesl-1S IR at the cortical regions of the neuronal somata. Immunofluorescent observations using antisynaptophysin and anti-Vesl-1S antibodies, and electron microscopic observations, revealed that Vesl-1S accumulated at postsynaptic regions following PMA application. Membrane depolarization with high concentrations of external potassium also promoted the punctate distribution of Vesl-1S IR. These results demonstrate that phorbol-triggered reaction cascades result in the accumulation of Ves-1S protein at postsynaptic regions, and suggest that these phorbol effects may mimic those caused by synaptic activities.