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      Inhibition of the calcium- and voltage-dependent big conductance potassium channel ameliorates cisplatin-induced apoptosis in spiral ligament fibrocytes of the cochlea.

      Neuroscience
      Animals, Annexin A5, metabolism, Apoptosis, drug effects, Cells, Cultured, Cisplatin, antagonists & inhibitors, toxicity, Cochlea, cytology, Electrophysiology, Female, Flow Cytometry, Gerbillinae, Large-Conductance Calcium-Activated Potassium Channels, Male, Microscopy, Fluorescence, Microscopy, Phase-Contrast, Nerve Fibers, Patch-Clamp Techniques, Potassium Channel Blockers, pharmacology, Potassium Channels, Voltage-Gated

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          Abstract

          The role of calcium- and voltage-dependent big conductance potassium channels in regulating apoptosis was investigated in cultured type I spiral ligament fibrocytes. Incubation of type I spiral ligament fibrocytes derived from gerbil cochlea with cisplatin induced dose- and time-dependent apoptosis as demonstrated by annexin V conjugated to fluorescein isothiocyanate/prodidium iodide assays. The average voltage activation threshold of whole cell current was sharply shifted to -40 mV in the cisplatin-treated cells as compared with a value of 40 mV in control cells. The average whole-cell current of cisplatin-treated cells induced by a depolarization voltage step from -80 to -10 mV was increased significantly to 1.2+/-0.4 nA as compared with 0.08+/-0.1 nA in control cells. Coincubation with tetraethylammonium and cisplatin retained the whole cell current in the normal range (0.12+/-0.2 nA). The increment of cisplatin-induced whole-cell current was inhibited (97+/-5%) by a specific calcium- and voltage-dependent big conductance potassium channel blocker iberiotoxin. Consistent with this, co-incubation with tetraethylammonium significantly attenuated cisplatin-induced apoptosis in type I spiral ligament fibrocytes by more than 50%. We conclude that the activation of BK channels is an early event associated with cisplatin-induced apoptosis in type I spiral ligament fibrocytes. These findings also point to the calcium- and voltage-dependent big conductance potassium channels as a potential pharmacological target for manipulating cisplatin ototoxicity.

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