Curcumin: A new cell-permeant inhibitor of the inositol 1,4,5-triphosphate receptor

Curcumin (diferuoylmethane or 1,7-bis (4-hydroxy-3-methoxyphenol)-1,6-hepatadiene-3,5-dione) is the active ingredient of the spice turmeric. Curcumin has been shown to have a number of pharmacological and therapeutic uses. This study shows that curcumin is a potent inhibitor of the inositol 1,4,5-trisphosphate-sensitive Ca²⁺ channel (InsP₃ receptor). In porcine cerebellar microsomes, the extent of InsP₃-induced Ca²⁺ release (IICR) is almost completely inhibited by 50 μM curcumin (IC₅₀=10μM). As the extent of IICR cannot be restored back to control levels by the addition of excess InsP₃ and since it has little effect on [³H]InsP₃ binding to cerebellar microsomes, this inhibition is likely to be non-competitive in nature. IICR in cerebellar microsomes is biphasic consisting of a fast and slow component. The rate constants for the two components are both reduced by curcumin to similar extents (by about 70% of control values at 40 μM curcumin). In addition, curcumin also reduces agonist (ATP)-stimulated Ca²⁺ mobilization from intact HL-60 cells, indicating that curcumin is cell permeant. However, since it also affects intracellular Ca²⁺ pumps and possibly ryanodine receptors, it may lead to complex Ca²⁺ transient responses within cells, which may well explain some of its putative therapeutic properties.