We have previously reported that paraoxon, an organophosphate compound, at submicromolar concentrations effectively suppresses Ca2+ action potentials and modulates the activity of snail neurons. This effect was unrelated to acetylcholinesterase inhibition but was found to involve the direct or indirect modulation of ion channels [Vatanparast, J., Janahmadi, M., Asgari, A.R., Sepehri, H., Haeri-Rohani, A., 2006a. Paraoxon suppresses Ca2+ action potential and afterhyperpolarization in snail neurons: Relevance to the hyperexcitability induction. Brain Res. 1083 (1), 110-117]. In the present work, the interaction of paraoxon with protein kinase C (PKC) and inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ release, on the modulation of Ca2+ action potentials and neuronal activity was investigated. Phorbol 12, 13 dibutyrate (PdBu), the activator of PKC, suppressed afterhyperpolarization and increased the activity of snail neurons without any significant effect on the Ca2+ action potential duration. Pretreatment with PKC activator attenuated the suppressing effect of paraoxon on the duration of Ca2+ action potentials. Staurosporine, a selective blocker of PKC, did not block the effect of paraoxon on Ca2+ action potential suppression and hyperexcitability induction. Our findings did not support the involvement PKC in the paraoxon induced Ca2+ action potential suppression and neuronal activity modulation, although activation of this protein kinase could attenuate some effects of paraoxon. Pretreatment with 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8), an antagonist of IP3-mediated Ca2+ release, abolished the secondary silencing effect of paraoxon, which is observed after primary paraoxon-induced hyperexcitability. It was concluded that slow activation of intracellular cascades by paraoxon could induce an IP3 mediated Ca2+ release from intracellular stores and participate to its secondary silencing effect by mechanisms dependent on intracellular calcium homeostasis.