Cisplatin activates volume sensitive LRRC8 channel mediated currents in Xenopus oocytes

IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
A. Gradogna, Héctor Gaitán-Peñas, A. Boccaccio, R. Estévez, M. Pusch
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引用次数: 15

Abstract

ABSTRACT LRRC8 proteins have been shown to underlie the ubiquitous volume regulated anion channel (VRAC). VRAC channels are composed of the LRRC8A subunit and at least one among the LRRC8B-E subunits. In addition to their role in volume regulation, LRRC8 proteins have been implicated in the uptake of chemotherapeutic agents. We had found that LRRC8 channels can be conveniently expressed in Xenopus oocytes, a system without endogenous VRAC activity. The fusion with fluorescent proteins yielded constitutive activity for A/C, A/D and A/E heteromers. Here we tested the effect of the anticancer drug cisplatin on LRRC8A-VFP/8E-mCherry and LRRC8A-VFP/8D-mCherry co-expressing oocytes. Incubation with cisplatin dramatically activated currents for both subunit combinations, confirming that VRAC channels provide an uptake pathway for cisplatin and that intracellular cisplatin accumulation strongly activates the channels. Thus, specific activators of LRRC8 proteins might be useful tools to counteract chemotherapeutic drug resistance.
顺铂激活爪蟾卵母细胞中LRRC8通道介导的体积敏感电流
LRRC8蛋白已被证明是普遍存在的体积调节阴离子通道(VRAC)的基础。VRAC通道由LRRC8A亚基和LRRC8B-E亚基中的至少一个组成。除了在体积调节中的作用外,LRRC8蛋白还与化疗药物的摄取有关。我们发现,LRRC8通道在非洲爪蟾卵母细胞中可以方便地表达,这是一个没有内源性VRAC活性的系统。与荧光蛋白的融合产生了A/C、A/D和A/E异构体的组成活性。我们测试了抗癌药物顺铂对LRRC8A-VFP/8E-mCherry和LRRC8A-VFP/8D-mCherry共表达卵母细胞的影响。顺铂的孵育显著激活了两种亚基组合的电流,证实了VRAC通道提供了顺铂的摄取途径,细胞内的顺铂积累强烈激活了通道。因此,LRRC8蛋白的特异性激活剂可能是对抗化疗耐药的有用工具。
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来源期刊
Channels
Channels 生物-生化与分子生物学
CiteScore
5.90
自引率
0.00%
发文量
21
审稿时长
6-12 weeks
期刊介绍: Channels is an open access journal for all aspects of ion channel research. The journal publishes high quality papers that shed new light on ion channel and ion transporter/exchanger function, structure, biophysics, pharmacology, and regulation in health and disease. Channels welcomes interdisciplinary approaches that address ion channel physiology in areas such as neuroscience, cardiovascular sciences, cancer research, endocrinology, and gastroenterology. Our aim is to foster communication among the ion channel and transporter communities and facilitate the advancement of the field.
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