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Pharmacological modulation of transmitter release by inhibition of pressure-dependent potassium currents in vestibular hair cells

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Abstract

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.

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Acknowledgment

The study was supported by a START grant by the Medical Faculty Aachen to T.H.

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Authors and Affiliations

  1. Institute of Physiology, Medical Faculty, RWTH Aachen, 52057, Aachen, Germany

    Thorsten Haasler, Georg Homann, Eberhard Jüngling & Andreas Lückhoff

  2. Department of Oto-Laryngology and Plastic Head and Neck Surgery, RWTH University Aachen, 52057, Aachen, Germany

    Thorsten Haasler, Thien An Duong Dinh & Martin Westhofen

Authors
  1. Thorsten Haasler
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  2. Georg Homann
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  3. Thien An Duong Dinh
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  4. Eberhard Jüngling
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  5. Martin Westhofen
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  6. Andreas Lückhoff
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Corresponding author

Correspondence to Andreas Lückhoff.

Additional information

Thorsten Haasler and Georg Homann equally contributed to this work.

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Fig. 1

Supplemental effects of hydrostatic pressure on the voltage responses of a vestibular hair cell. a Stimulus protocol. Currents of 700 pA were repetitively injected into the cell in current clamp mode. b Superpose traces, the first one obtained at an elevated hydrostatic pressure of 0.5 cm H2O and the second one at the standard hydrostatic pressure of 0.2 cm H2O. c Effects of charybdotoxin (CTx 100 nM; preincubation 2 min; GIF 73.1 kb)

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Haasler, T., Homann, G., Duong Dinh, T.A. et al. Pharmacological modulation of transmitter release by inhibition of pressure-dependent potassium currents in vestibular hair cells. Naunyn-Schmied Arch Pharmacol 380, 531–538 (2009). https://doi.org/10.1007/s00210-009-0463-3

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  • DOI: https://doi.org/10.1007/s00210-009-0463-3

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