Different uptake of gentamicin through TRPV1 and TRPV4 channels determines cochlear hair cell vulnerability.
Different uptake of gentamicin through TRPV1 and TRPV4 channels determines cochlear hair cell vulnerability.
复制标题
DOI：
10.1038/emm.2013.25
复制
发表时间：
2013-03-08
影响因子：
12.8
通讯作者：
Park, Raekil
中科院分区：
文献类型：
--
作者：
Lee, Jeong-Han;Park, Channy;Kim, Se-Jin;Kim, Hyung-Jin;Oh, Gi-Su;Shen, AiHua;So, Hong-Seob;Park, Raekil
耳蜗底部的毛细胞似乎比顶端的毛细胞更容易受到氨基糖苷类庆大霉素的损伤。然而，庆大霉素的基底部至心尖部梯度耳毒性机制仍有待阐明。我们在这里报告，庆大霉素引起啮齿动物耳蜗毛细胞损伤的时间和剂量依赖性的方式。基转毛细胞比顶转毛细胞更易受庆大霉素的影响。庆大霉素结合德克萨斯红（GTTR）的摄取主要在新生大鼠的基底毛细胞。瞬时受体电位香草酸1（TRPV1）和4（TRPV4）的表达被证实在表皮板，静纤毛和毛细胞体的内毛细胞和外毛细胞。TRPV1和TRPV4参与庆大霉素的毛细胞运输被证实，外源性钙处理和TRPV抑制剂，包括钆和钌红，导致显着抑制GTTR摄取和庆大霉素诱导的毛细胞损伤在啮齿动物和斑马鱼耳毒性模型系统。这些结果表明，耳蜗毛细胞的细胞毒性的脆弱性，在基础转向庆大霉素可能取决于有效的药物，这是，在一定程度上，介导的TRPV1和TRPV4蛋白的摄取。
Hair cells at the base of the cochlea appear to be more susceptible to damage by the aminoglycoside gentamicin than those at the apex. However, the mechanism of base-to-apex gradient ototoxicity by gentamicin remains to be elucidated. We report here that gentamicin caused rodent cochlear hair cell damages in a time- and dose-dependent manner. Hair cells at the basal turn were more vulnerable to gentamicin than those at the apical turn. Gentamicin-conjugated Texas Red (GTTR) uptake was predominant in basal turn hair cells in neonatal rats. Transient receptor potential vanilloid 1 (TRPV1) and 4 (TRPV4) expression was confirmed in the cuticular plate, stereocilia and hair cell body of inner hair cells and outer hair cells. The involvement of TRPV1 and TRPV4 in gentamicin trafficking of hair cells was confirmed by exogenous calcium treatment and TRPV inhibitors, including gadolinium and ruthenium red, which resulted in markedly inhibited GTTR uptake and gentamicin-induced hair cell damage in rodent and zebrafish ototoxic model systems. These results indicate that the cytotoxic vulnerability of cochlear hair cells in the basal turn to gentamicin may depend on effective uptake of the drug, which was, in part, mediated by the TRPV1 and TRPV4 proteins.
登录
查看更多内容
DOI：
10.1007/s10162-002-3022-x
发表时间：
2003-06-01
影响因子：
2.4
作者：
Harris, JA;Cheng, AG;Rubel, EW
通讯作者：
Rubel, EW
DOI：
10.1073/pnas.93.24.14146
发表时间：
1996-11-26
影响因子：
11.1
作者：
Gillo, B;Chorna, I;Minke, B
通讯作者：
Minke, B
影响因子：
2.8
作者：
Kamimura, T;Whitworth, CA;Rybak, LP
通讯作者：
Rybak, LP
影响因子：
2.8
作者：
DEGROOT, JCMJ;MEEUWSEN, F;VELDMAN, JE
通讯作者：
VELDMAN, JE
影响因子：
2.8
作者：
FORGE, A;WRIGHT, A;DAVIES, SJ
通讯作者：
DAVIES, SJ