Inhibition of calmodulin (CaM) sensitizes Ca²⁺ release mediated by D-myo-inositol (1,4,5)-trisphosphate (InsP ₃) in Xenopus oocytes, which results in spontaneous Ca²⁺-dependent Cl^– current oscillations or in a shift of the concentration threshold for lysophosphatidic acid (LPA) by a tenfold factor. The oscillatory currents appear at a low initial Ca²⁺ concentration and without any significant increase in the inositol phosphate (InsPs) concentrations. These data led us to rule out the direct involvement of CaM, as well as the implied involvement of InsP ₃ 3-kinase. The response to intracellular injection of the non-metabolizable InsP ₃ analog 3-deoxy-3-fluoro InsP ₃ (InsP ₃-F) is obviously affected by previous treatment with CaM inhibitory peptide. Furthermore, these effects have been consistently obtained with specific CaMKII inhibitors such as KN-93 and AIP. CaM plays a key role in the Ca²⁺-dependent inactivation of type I InsP ₃ receptors. The experiments presented hereby allow us to postulate that CaM could also exert its inhibitory effect through CaMKII in a way that does not involve InsP ₃ metabolism regulation. It is concluded that CaMKII could participate in Ca²⁺-evoked inhibition of InsP ₃-mediated Ca²⁺ release by inhibiting the InsP ₃ receptor.