Ca 2+ -independent inhibition of inositol trisphosphate receptors by calmodulin: Redistribution of calmodulin as a possible means of regulating Ca 2+ mobilization

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Abstract
The interactions between calmodulin, inositol 1,4,5-trisphosphate (Ins P 3 ), and pure cerebellar Ins P 3 receptors were characterized by using a scintillation proximity assay. In the absence of Ca 2+ , 125 I-labeled calmodulin reversibly bound to multiple sites on Ins P 3 receptors and Ca 2+ increased the binding by 190% ± 10%; the half-maximal effect occurred when the Ca 2+ concentration was 184 ± 14 nM. In the absence of Ca 2+ , calmodulin caused a reversible, concentration-dependent (IC 50 = 3.1 ± 0.2 μM) inhibition of [ 3 H]Ins P 3 binding by decreasing the affinity of the receptor for Ins P 3 . This effect was similar at all Ca 2+ concentrations, indicating that the site through which calmodulin inhibits Ins P 3 binding has similar affinities for calmodulin and Ca 2+ -calmodulin. Calmodulin (10 μM) inhibited the Ca 2+ release from cerebellar microsomes evoked by submaximal, but not by maximal, concentrations of Ins P 3 . Tonic inhibition of Ins P 3 receptors by the high concentrations of calmodulin within cerebellar Purkinje cells may account for their relative insensitivity to Ins P 3 and limit spontaneous activation of Ins P 3 receptors in the dendritic spines. Inhibition of Ins P 3 receptors by calmodulin at all cytosolic Ca 2+ concentrations, together with the known redistribution of neuronal calmodulin evoked by protein kinases and Ca 2+ , suggests that calmodulin may also allow both feedback control of Ins P 3 receptors and integration of inputs from other signaling pathways.