Suppression of delayed rectifier K+ channels by gentamicin induces membrane hyperexcitability through JNK and PKA signaling pathways in vestibular ganglion neurons.
Suppression of delayed rectifier K+ channels by gentamicin induces membrane hyperexcitability through JNK and PKA signaling pathways in vestibular ganglion neurons.
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DOI：
10.1016/j.biopha.2020.111185
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发表时间：
2021-01
期刊：
影响因子：
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通讯作者：
Yunmei Zhang;Yuan Zhang;Zizhang Wang;Yufang Sun;Xinghong Jiang;Man Xue;Yafeng Yu;J. Tao
中科院分区：
文献类型：
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作者：
Yunmei Zhang;Yuan Zhang;Zizhang Wang;Yufang Sun;Xinghong Jiang;Man Xue;Yafeng Yu;J. Tao
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，到目前为止，潜在的细胞和分子机制仍不清楚。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）神经元的持续延迟整流钾电流（IDR）和膜兴奋性的作用。结果表明，庆大霉素可使VG神经元的IDR呈浓度依赖性降低，而对瞬时外向A型K+电流（IA）无影响。庆大霉素引起的IDR降低不依赖于G蛋白活性，并导致失活Vhalf的超极化移动。对磷酸化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则不受影响。用α-树毒素阻断Kv 1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IDR降低。JNK信号的拮抗减弱了庆大霉素诱导的PKA活性的刺激，而PKA抑制则阻止了庆大霉素诱导的IDR反应。此外，庆大霉素显着增加的数量的动作电位发射相位和紧张性放电型神经元;预处理VG神经元与JNK抑制剂II和theIDR的封锁取消了这种效果。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IDR。这种庆大霉素诱导的IDR反应介导VG神经元的过度兴奋，并可能有助于其药理学前庭效应。
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 (IDR) and membrane excitability in vestibular ganglion (VG) neurons in mice. Our results showed that the application of gentamicin to VG neurons decreased theIDRin a concentration-dependent manner, while the transient outward A-type K+current (IA) remained unaffected. The decrease inIDRinduced by gentamicin was independent of G-protein activity and led to a hyperpolarizing shift of the inactivationVhalf. The analysis of phospho-c-Jun N-terminal kinase (p-JNK) revealed that gentamicin significantly stimulated JNK, whilep-ERK andp-p38 remained unaffected. Blocking Kv1 channels with α-dendrotoxin or pretreating VG neurons with the JNK inhibitor II abrogated the gentamicin-induced decrease inIDR. Antagonism of JNK signaling attenuated the gentamicin-induced stimulation of PKA activity, whereas PKA inhibition prevented theIDRresponse 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 theIDRabolished this effect. Taken together, our results demonstrate that gentamicin decreases theIDRthrough a G-protein-independent but JNK and PKA-mediated signaling pathways. This gentamicin-inducedIDRresponse mediates VG neuronal hyperexcitability and might contribute to its pharmacological vestibular effects.