The effects of thimerosal on calcium uptake and inositol 1,4,5-trisphosphate-induced calcium release in cerebellar microsomes

Thimerosal inhibits calcium uptake in skeletal muscle sarcoplasmic reticulum and rat cerebellar microsomes by inhibiting the Ca²⁺-ATPase. In the presence of 5 mM dithiothreitol (DTT), Ca²⁺ uptake and ATPase activity were not inhibited by thimerosal, indicating that thimerosal modifies cysteine residues of the Ca²⁺-ATPase. Low thimerosal concentrations (2μM) sensitize the inositol 1,4,5-trisphosphate (InsP₃)-sensitive Ca²⁺ channel, making it open at lower InsP₃ concentrations. Higher concentrations of thimerosal, however, cause inhibition of InsP₃-induced Ca²⁺ release. Both synthesization and inhibition of the InsP₃ receptor by thimerosal can be prevented by DTT. The binding and metabolism of InsP₃ by cerebellar microsomes is not affected by thimerosal. The amount of InsP₃-induced Ca²⁺ release is co-operatively linked to the InsP₃ concentration with a Hill coefficient of 2.0 ± 0.3. This is decreased to 1.0 ± 0.2 at inhibitory concentrations of thimerosal. Under our experimental conditions, we observed no dependence of quantal Ca²⁺ release on intraluminial Ca²⁺ concentration.