Regulation of InsP3-mediated Ca2+ release by CaMKII in Xenopus oocytes.

Inhibition of calmodulin (CaM) sensitizes Ca2+ release mediated by D-myo-inositol (1,4,5)-trisphosphate (InsP3) in Xenoplus 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 InsP3 3-kinase. The response to intracellular injection of the non-metabolizable InsP3 analog 3-deoxy-3-fluoro InsP3 (InsP3-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 InsP3 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 InsP3 metabolism regulation. It is concluded that CaMKII could participate in Ca2+-evoked inhibition of InsP3-mediated Ca2+ release by inhibiting the InsP3 receptor.