| First Author | Meena AS | Year | 2022 |
| Journal | Cell Rep | Volume | 39 |
| Issue | 11 | Pages | 110937 |
| PubMed ID | 35705057 | Mgi Jnum | J:326051 |
| Mgi Id | MGI:7294000 | Doi | 10.1016/j.celrep.2022.110937 |
| Citation | Meena AS, et al. (2022) TRPV6 channel mediates alcohol-induced gut barrier dysfunction and systemic response. Cell Rep 39(11):110937 |
| abstractText | 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. |
