TRPV6 channel mediates alcohol-induced gut barrier dysfunction and systemic response

作者：Avtar S. Meena, Pradeep K. Shukla, Briar Bell, Francesco Giorgianni, Rebeca Caires, Carlos Fernández‐Peña, Sarka Beranova, Eitaro Aihara, Marshall H. Montrose, Mehdi Chaib, Liza Makowski, Indira Neeli, Marko Radic, Valeria Vásquez, Jonathan H. Jaggar, Julio F. Cordero-Morales, Radhakrishna Rao · 发表于：Cell Reports · 年份：2022 · DOI：10.1016/j.celrep.2022.110937 · 被引用次数：42 · 研究领域：Alcohol Consumption and Health Effects、Biochemical effects in animals、Ion Channels and Receptors

Intestinal epithelial tight junction disruption is a primary contributing factor in alcohol-associated endotoxemia, systemic inflammation, and multiple organ damage. Ethanol and acetaldehyde disrupt tight junctions by elevating intracellular Ca 2+ . Here we identify TRPV6, a Ca 2+ -permeable channel, as responsible for alcohol-induced elevation of intracellular Ca 2+ , intestinal barrier dysfunction, and systemic inflammation. Ethanol and acetaldehyde elicit TRPV6 ionic currents in Caco-2 cells. Studies in Caco-2 cell monolayers and mouse intestinal organoids show that TRPV6 deficiency or inhibition attenuates ethanol- and acetaldehyde-induced Ca 2+ influx, tight junction disruption, and barrier dysfunction. Moreover, Trpv6 −/− mice are resistant to alcohol-induced intestinal barrier dysfunction. Photoaffinity labeling of 3-azibutanol identifies a histidine as a potential alcohol-binding site in TRPV6. The substitution of this histidine, and a nearby arginine, reduces ethanol-activated currents. Our findings reveal that TRPV6 is required for alcohol-induced gut barrier dysfunction and inflammation. Molecules that decrease TRPV6 function have the potential to attenuate alcohol-associated tissue injury.