Purified reconstituted inositol 1,4,5-trisphosphate receptors. Thiol reagents act directly on receptor protein

Thimerosal, a sulfhydryl oxidizing reagent, has been shown to induce Ca²⁺ mobilization in several cell types and to increase the sensitivity of intracellular Ca²⁺ stores to inositol 1,4,5-trisphosphate (IP₃). Using purified IP₃ receptor (IP₃R) protein reconstituted in vesicles, we demonstrate pronounced stimulation by thimerosal of its Ca²⁺ channel activity. Effects of thimerosal are dependent on the redox state of the receptor, implying an action of thimerosal on a critical sulfhydryl group(s) of IP₃R. Thimerosal enhances the affinity of IP₃R for IP₃ binding. The manner in which thimerosal modulates IP₃R responsiveness to IP₃ provides evidence for receptor heterogeneity with implications for mechanisms of quantal Ca²⁺ release. These results clarify regulation of IP₃R activity by redox modulation.