Department of Otolaryngology, the First Affiliated Hospital of Soochow University, Suzhou 215006, PR China; Department of Physiology and Neurobiology & Centre for Ion Channelopathy, Medical College of Soochow University, Suzhou 215123, PR China.
Department of Geriatrics & Institute of Neuroscience, the Second Affiliated Hospital of Soochow University, Suzhou 215004, PR China; Department of Physiology and Neurobiology & Centre for Ion Channelopathy, Medical College of Soochow University, Suzhou 215123, PR China.
Biomed Pharmacother. 2021 Mar;135:111185. doi: 10.1016/j.biopha.2020.111185. Epub 2021 Feb 1.
Aminoglycoside antibiotics, such as gentamicin, are known to have vestibulotoxic effects, including ataxia and disequilibrium. To date, however, the underlying cellular and molecular mechanisms are still unclear. In this study, we determined the role of gentamicin in regulating the sustained delayed rectifier K current (I) and membrane excitability in vestibular ganglion (VG) neurons in mice. Our results showed that the application of gentamicin to VG neurons decreased the I in a concentration-dependent manner, while the transient outward A-type K current (I) remained unaffected. The decrease in I induced by gentamicin was independent of G-protein activity and led to a hyperpolarizing shift of the inactivation V. The analysis of phospho-c-Jun N-terminal kinase (p-JNK) revealed that gentamicin significantly stimulated JNK, while p-ERK and p-p38 remained unaffected. Blocking Kv1 channels with α-dendrotoxin or pretreating VG neurons with the JNK inhibitor II abrogated the gentamicin-induced decrease in I. Antagonism of JNK signaling attenuated the gentamicin-induced stimulation of PKA activity, whereas PKA inhibition prevented the I response induced by gentamicin. Moreover, gentamicin significantly increased the number of action potentials fired in both phasic and tonic firing type neurons; pretreating VG neurons with the JNK inhibitor II and the blockade of the I abolished this effect. Taken together, our results demonstrate that gentamicin decreases the I through a G-protein-independent but JNK and PKA-mediated signaling pathways. This gentamicin-induced I response mediates VG neuronal hyperexcitability and might contribute to its pharmacological vestibular effects.
氨基糖苷类抗生素，如庆大霉素，已知具有前庭毒性作用，包括共济失调和平衡失调。然而，迄今为止，其潜在的细胞和分子机制尚不清楚。在这项研究中，我们确定了庆大霉素在调节小鼠前庭神经节（VG）神经元中的持续延迟整流钾电流（I）和膜兴奋性中的作用。我们的结果表明，庆大霉素以浓度依赖性方式降低 I，而瞬时外向 A 型钾电流（I）保持不变。庆大霉素引起的 I 减少与 G 蛋白活性无关，并导致失活 V 的超极化偏移。磷酸化 c-Jun N 末端激酶（p-JNK）的分析表明，庆大霉素显著刺激 JNK，而 p-ERK 和 p-p38 保持不变。用α-树突毒素阻断 Kv1 通道或用 JNK 抑制剂 II 预处理 VG 神经元可消除庆大霉素引起的 I 减少。阻断 JNK 信号减弱了庆大霉素诱导的 PKA 活性的刺激，而 PKA 抑制可防止庆大霉素诱导的 I 反应。此外，庆大霉素显著增加了在相性和紧张性放电型神经元中触发的动作电位的数量；用 JNK 抑制剂 II 预处理 VG 神经元和阻断 I 可消除这种作用。总之，我们的结果表明，庆大霉素通过 G 蛋白非依赖性但 JNK 和 PKA 介导的信号通路降低 I。这种庆大霉素诱导的 I 反应介导了 VG 神经元的过度兴奋，可能有助于其药理学前庭效应。
