Depolarization and decreased surface expression of K + channels contribute to NSAID-inhibition of intestinal restitution

Non-steroidal anti-inflammatory drugs (NSAIDs) contribute to gastrointestinal ulcer formation by inhibiting epithelial cell migration and mucosal restitution; however, the drug-affected signaling pathways are poorly defined. We investigated whether NSAID inhibition of intestinal epithelial migration...

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Veröffentlicht in:Biochemical pharmacology 2007-06, Vol.74 (1), p.74-85
Hauptverfasser: Freeman, L.C., Narvaez, D.F., McCoy, A., von Stein, F.B., Young, S., Silver, K., Ganta, S., Koch, D., Hunter, R., Gilmour, R.F., Lillich, J.D.
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Sprache:eng
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Zusammenfassung:Non-steroidal anti-inflammatory drugs (NSAIDs) contribute to gastrointestinal ulcer formation by inhibiting epithelial cell migration and mucosal restitution; however, the drug-affected signaling pathways are poorly defined. We investigated whether NSAID inhibition of intestinal epithelial migration is associated with depletion of intracellular polyamines, depolarization of membrane potential ( E m) and altered surface expression of K + channels. Epithelial cell migration in response to the wounding of confluent IEC-6 and IEC-Cdx2 monolayers was reduced by indomethacin (100 μM), phenylbutazone (100 μM) and NS-398 (100 μM) but not by SC-560 (1 μM). NSAID-inhibition of intestinal cell migration was not associated with depletion of intracellular polyamines. Treatment of IEC-6 and IEC-Cdx2 cells with indomethacin, phenylbutazone and NS-398 induced significant depolarization of E m, whereas treatment with SC-560 had no effect on E m. The E m of IEC-Cdx2 cells was: −38.5 ± 1.8 mV under control conditions; −35.9 ± 1.6 mV after treatment with SC-560; −18.8 ± 1.2 mV after treatment with indomethacin; and −23.7 ± 1.4 mV after treatment with NS-398. Whereas SC-560 had no significant effects on the total cellular expression of K v1.4 channel protein, indomethacin and NS-398 decreased not only the total cellular expression of K v1.4, but also the cell surface expression of both K v1.4 and K v1.6 channel subunits in IEC-Cdx2. Both K v1.4 and K v1.6 channel proteins were immunoprecipitated by K v1.4 antibody from IEC-Cdx2 lysates, indicating that these subunits co-assemble to form heteromeric K v channels. These results suggest that NSAID inhibition of epithelial cell migration is independent of polyamine-depletion, and is associated with depolarization of E m and decreased surface expression of heteromeric K v1 channels.
ISSN:0006-2952
1873-2968
DOI:10.1016/j.bcp.2007.03.030