Hair cell uptake of gentamicin in the developing mouse utricle,Journal of Cellular Physiology

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Hair cell uptake of gentamicin in the developing mouse utricle
Journal of Cellular Physiology ( IF 4.5 ) Pub Date : 2020-12-23 , DOI: 10.1002/jcp.30228
Xiaoqing Qian _{1,

2} , Ziyu He _{1,

2} , Yanmei Wang _{1,

2} , Binjun Chen _{1,

2} , Alisa Hetrick ₃ , Chunfu Dai _{1,

2} , Fanglu Chi _{1,

2} , Hongzhe Li _{3,

4} , Dongdong Ren _{1,

2}

Affiliation

Intratympanic injection of gentamicin has proven to be an effective therapy for intractable vestibular dysfunction. However, most studies to date have focused on the cochlea, so little is known about the distribution and uptake of gentamicin by the counterpart of the auditory system, specifically vestibular hair cells (HCs). Here, with a combination of in vivo and in vitro approaches, we used a gentamicin‐Texas Red (GTTR) conjugate to investigate the mechanisms of gentamicin vestibulotoxicity in the developing mammalian utricular HCs. In vivo, GTTR fluorescence was concentrated in the apical cytoplasm and the cellular membrane of neonatal utricular HCs, but scarce in the nucleus of HCs and supporting cells. Quantitative analysis showed the GTTR uptake by striolar HCs was significantly higher than that in the extrastriola. In addition, the GTTR fluorescence intensity in the striola was increased gradually from 1 to 8 days, peaking at 8–9 days postnatally. In vitro, utricle explants were incubated with GTTR and candidate uptake conduits, including mechanotransduction (MET) channels and endocytosis in the HC, were inhibited separately. GTTR uptake by HCs could be inhibited by quinine, a blocker of MET channels, under both normal and stressed conditions. Meanwhile, endocytic inhibition only reduced GTTR uptake in the CoCl₂ hypoxia model. In sum, the maturation of MET channels mediated uptake of GTTR into vestibular HCs. Under stressed conditions, MET channels play a pronounced role, manifested by channel‐dependent stress enhanced GTTR permeation, while endocytosis participates in GTTR entry in a more selective manner.

中文翻译：

正在发育的小鼠椭圆囊中庆大霉素的毛细胞摄取

鼓室内注射庆大霉素已被证明是治疗顽固性前庭功能障碍的有效方法。然而，迄今为止，大多数研究都集中在耳蜗上，因此对听觉系统对应物（特别是前庭毛细胞 (HC)）庆大霉素的分布和摄取知之甚少。在这里，结合体内和体外方法，我们使用庆大霉素-德克萨斯红 (GTTR) 偶联物来研究庆大霉素前庭毒性在发育中的哺乳动物椭圆囊中的机制。在体内，GTTR荧光主要集中在新生儿囊状HCs的顶端细胞质和细胞膜中，而在HCs的细胞核和支持细胞中很少。定量分析表明，纹状体 HCs 的 GTTR 摄取显着高于 extrastriola 中的 GTTR 吸收。此外，Striola 中的 GTTR 荧光强度从 1 到 8 天逐渐增加，在出生后 8 到 9 天达到峰值。在体外，胞囊外植体与 GTTR 一起孵育，候选摄取管道，包括机械转导 (MET) 通道和 HC 中的内吞作用，分别受到抑制。在正常和压力条件下，HCs 对 GTTR 的吸收可以被奎宁抑制，奎宁是 MET 通道的阻滞剂。同时，内吞抑制仅减少了 CoCl 中的 GTTR 摄取在正常和压力条件下。同时，内吞抑制仅减少了 CoCl 中的 GTTR 摄取在正常和压力条件下。同时，内吞抑制仅减少了 CoCl 中的 GTTR 摄取₂缺氧模型。总之，MET 通道的成熟介导 GTTR 吸收到前庭 HCs 中。在压力条件下，MET 通道发挥显着作用，表现为通道依赖性压力增强 GTTR 渗透，而内吞作用以更具选择性的方式参与 GTTR 进入。

更新日期：2020-12-23

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