| Autor: |
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 Z. Radic, Valeria Vásquez, Jonathan H. Jaggar, Julio F. Cordero-Morales, RadhaKrishna Rao |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
Cell Reports, Vol 39, Iss 11, Pp 110937- (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2022.110937 |
| Popis: |
Summary: 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 Ca2+. Here we identify TRPV6, a Ca2+-permeable channel, as responsible for alcohol-induced elevation of intracellular Ca2+, 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 Ca2+ 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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