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Thiol-Reactive Agents Biphasically Regulate Inositol 1,4,5-Trisphosphate Binding and Ca²⁺ Release Activities in Bovine Adrenal Cortex Microsomes¹

Department of Pharmacology, Faculty of Medicine, University of Sherbrooke, Sherbrooke Québec, Canada J1H 5N4

Address all correspondence and requests for reprints to: Dr. Gaétan Guillemette, Department of Pharmacology, Faculty of Medicine, University of Sherbrooke, 3001, 12^e Avenue Nord, Sherbrooke, Québec, Canada J1H 5N4. E-mail: gguillem{at}courrier.usherb.ca

Within all endocrine cells, the inositol 1,4,5-trisphosphate (InsP₃) receptor plays an important role in regulation of the intracellular Ca²⁺ concentration. In the present study we showed that a single short-term treatment with either N-ethylmaleimide (known to decrease InsP₃ receptor activity) or thimerosal (known to increase InsP₃ receptor activity) caused time-dependent biphasic effects on the InsP₃ binding activity of bovine adrenal cortex microsomes. The early potentiating effect of thiol-reactive agents translated into a 2-fold increase in binding affinity and Ca²⁺ release efficiency. The late dampening effect of thiol-reactive agents translated into a continuous reduction of the maximal binding capacity of the microsomes with a concomitant decrease in Ca²⁺ release efficiency. Under these conditions, Western blot analyses demonstrated that the level of InsP₃ receptor protein was not modified. Sequential treatments with thimerosal and the reducing agent dithiothreitol showed that the InsP₃ receptor can readily oscillate between high and low affinity states that are related to its alkylation state. Our results suggest a common mode of action of thiol-reactive agents on the InsP₃ receptor. These results also support the contention that cellular mechanisms of thiol group modification could play important roles in regulation of the intracellular Ca²⁺ concentration.