The thiol-oxidizing reagent, thimerosal, has been shown to increase the intracellular Ca concentration, to induce Ca spikes in several cell types, and to increase the sensitivity of intracellular Ca stores to inositol 1,4,5-trisphosphate. Ryanodine-sensitive stores have also been implicated in the generation of Ca oscillations induced by the addition of thimerosal. Here we report that micromolar concentrations of thimerosal stimulate Ca release from skeletal muscle sarcoplasmic reticulum vesicles, inhibit high affinity [H]ryanodine binding, and modify the channel activity of the reconstituted Ca release protein. Thimerosal inhibits ryanodine binding by decreasing the binding capacity (B) but does not affect the binding affinity or the dissociation rate of bound ryanodine. Single channel reconstitution experiments show that thimerosal (100-200 µM) stimulates single channel activity without modifying channel conductance. The thimerosal-stimulated channel is not inhibited by heparin. Furthermore, a Ca-stimulated channel is first activated and then inhibited in a time-dependent fashion by high concentrations of thimerosal (1 mM). Once inactivated, the channel cannot be reactivated by addition of either Ca or ATP.

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