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 |
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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. |
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ISSN: | 0006-2952 1873-2968 |
DOI: | 10.1016/j.bcp.2007.03.030 |