Journal
CHANNELS
Volume 11, Issue 3, Pages 254-260Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/19336950.2017.1284717
Keywords
anion; chloride channel; cisplatin; drug resistance; oocyte; volume regulation; VRAC
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Funding
- Fondazione Compagnia di San Paolo, Torino [2013.0922]
- European Leukodystrophies Association (ELA) Research Foundation [ELA2012-014C2B]
- Ministerio de Ciencia e Innovacion (MICINN) [SAF2015-70377]
- Generalitat de Catalunya [SGR2014-1178]
- Instituto de Salud Carlos III ERARE
- ICREA Academia prize
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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.
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