Pharmacological modulation of transmitter release by inhibition of pressure-dependent potassium currents in vestibular hair cells
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Vestibular vertigo may be induced by increases in the endolymphatic pressure that activate pressure-dependent K+ currents (IK,p) in vestibular hair cells. IK,p have been demonstrated to modulate transmitter release and are inhibited by low concentrations of cinnarizine. Beneficial effects against vestibular vertigo of cinnarizine have been attributed to its inhibition of calcium currents. Our aim was to determine the extent by which the inhibition of IK,p by cinnarizine may alter the voltage response to stimulating currents and to analyze whether such alterations may be sufficient to modulate the activation of Ca2+ currents and transmitter release. Vestibular type II hair cells from guinea pigs were studied using the whole-cell patch-clamp technique. In current clamp, voltage responses to trains of stimulating currents were recorded. In voltage clamp, transmitter release was assessed from changes in the cell capacitance, as calculated from the phase shift during application of sine waves. Cinnarizine (0.05–3 µM) concentration dependently reversed the depressing effects of increases in the hydrostatic pressure (from 0.2 to 0.5 cm H2O) on the voltage responses to stimulating currents. Voltage protocols that simulated these responses were applied in voltage clamp and revealed a significantly enhanced transmitter release in conditions mimicking an inhibition of IK,p. Cinnarizine (≤0.5 µM) did not inhibit calcium currents. We conclude that cinnarizine, in pharmacologically relevant concentrations, enhances transmitter release in the presence of elevated hydrostatic pressure by an indirect mechanism, involving inhibition of IK,p, enhancing depolarization, and increasing the voltage-dependent activation of Ca2+ currents, without directly affecting Ca2+ current.
KeywordsCapacitance Menière's disease Endolymphatic hydrops Ca2+ currents Patch clamp Current clamp Cinnarizine Charybdotoxin
The study was supported by a START grant by the Medical Faculty Aachen to T.H.
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