Voltage‐dependent ebselen and diorganochalcogenides inhibition of ⁴⁵Ca²⁺ influx into brain synaptosomes

Abstract

Abstract By mediating the Ca 2+ influx, Ca 2+ channels play a central role in neurotransmission. Chemical agents that potentially interfere with Ca 2+ homeostasis are potential toxic agents. In the present investigation, changes in Ca 2+ influx into synaptosomes by organic forms of selenium and tellurium were examined under nondepolarizing and depolarizing conditions induced by high KCl concentration (135 mM) or by 4‐aminopyridine (4‐AP). Under nondepolarizing conditions, ebselen (400 μM) increased Ca 2+ influx; diphenyl ditelluride (40–400 μM) decreased Ca 2+ in all concentrations tested; and diphenyl diselenide decreased Ca 2+ influx at 40 and 100 μM, but had no effect at 400 μM. In the presence of KCl as depolarizing agent, ebselen and diphenyl ditelluride decreased Ca 2+ influx in a linear fashion. In contrast, diphenyl diselenide did not modify Ca 2+ influx into isolated nerve terminals. In the presence of 4‐AP (3 mM) as depolarizing agent, ebselen (400 μM) caused a significant increase, whereas diphenyl diselenide and diphenyl ditelluride inhibited Ca 2+ influx into synaptosomes. The results can be explained by the fact that the mechanism through which 4‐AP and high K + induced elevation of intracellular Ca 2+ is not exactly coincident. The mechanism by which diphenyl ditelluride and ebselen interact with Ca 2+ channel is unknown, but may be related to reactivity with critical sulfhydryl groups in the protein complex. The results of the present study indicate that the effects of organochalcogenides were rather complex depending on the condition and the depolarizing agent used. © 2003 Wiley Periodicals, Inc. J Biochem Mol Toxicol 17:154–160, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10073