Journal
CELL REPORTS
Volume 39, Issue 11, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2022.110937
Keywords
-
Categories
Funding
- Veterans Administration [I01BX003014]
- National Institutes of Health [R01AA12307, R01DK55532, R01AA029270, R01GM133845, R01HL133745, R01HL155180, R01HL158846, R01GM125629]
Ask authors/readers for more resources
Intestinal epithelial tight junction disruption is a key factor in alcohol-induced endotoxemia, systemic inflammation, and organ damage. TRPV6, a Ca2+-permeable channel, is responsible for the elevation of intracellular Ca2+, intestinal barrier dysfunction, and systemic inflammation induced by alcohol. Inhibiting or deficient TRPV6 can attenuate alcohol-induced barrier dysfunction and Ca2+ influx.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available