The bell-shaped Ca2+ dependence of the inositol 1,4,5-trisphosphate-induced Ca2+ release is modulated by Ca2+/calmodulin

Calmodulin inhibits inositol 1,4,5-trisphosphate (IP3) binding to the IP3 receptor in both a Ca2+-dependent and a Ca2+-independent way. Because there are no functional data on the modulation of the IP3-induced Ca2+ release by calmodulin at various Ca2+ concentrations, we have studied how cytosolic Ca2+ and Sr2+ interfere with the effects of calmodulin on the IP3-induced Ca2+ release in permeabilized A7r5 cells, We now report that calmodulin inhibited Ca2+ release through the IP3 receptor with an IC50 of 4.6 mu M if the cytosolic Ca2+ concentration was 0.3 mu M or higher. This inhibition was particularly pronounced at low IP3 concentrations. In contrast, calmodulin did not affect IP3-induced Ca2+ release if the cytosolic Ca2+ concentration was below 0.3 mu M. Calmodulin also inhibited Ca2+ release through the IP3 receptor in the presence of at least 10 mu M Sr2+. We conclude that cytosolic Ca2+ or Sr2+ are absolutely required for the calmodulin-induced inhibition of the IP,induced Ca2+ release and that this dependence represents the formation of the Ca2+/calmodulin or Sr2+/ calmodulin complex.