Role of K(+) channel expression in polyamine-dependent intestinal epithelial cell migration |
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Authors: | Wang J Y Wang J Golovina V A Li L Platoshyn O Yuan J X |
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Institution: | Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. jwang@smail.umaryland.edu |
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Abstract: | Polyamines are essential for cell migrationduring early mucosal restitution after wounding in the gastrointestinaltract. Activity of voltage-gated K+ channels (Kv) controlsmembrane potential (Em) that regulates cytoplasmicfree Ca2+ concentration(Ca2+]cyt) by governing thedriving force for Ca2+ influx. This study determinedwhether polyamines are required for the stimulation of cell migrationby altering K+ channel gene expression,Em, andCa2+]cyt in intestinal epithelialcells (IEC-6). The specific inhibitor of polyamine synthesis, -difluoromethylornithine (DFMO, 5 mM), depleted cellularpolyamines (putrescine, spermidine, and spermine), selectivelyinhibited Kv1.1 channel (a delayed-rectifier Kv channel) expression,and resulted in membrane depolarization. Because IEC-6 cells did notexpress voltage-gated Ca2+ channels, the depolarizedEm in DFMO-treated cells decreased Ca2+]cyt as a result of reduceddriving force for Ca2+ influx through capacitativeCa2+ entry. Migration was reduced by 80% in thepolyamine-deficient cells. Exogenous spermidine not only reversed theeffects of DFMO on Kv1.1 channel expression, Em,and Ca2+]cyt but also restoredcell migration to normal. Removal of extracellular Ca2+ orblockade of Kv channels (by 4-aminopyridine, 1-5 mM) significantly inhibited normal cell migration and prevented the restoration of cellmigration by exogenous spermidine in polyamine-deficient cells. Theseresults suggest that polyamine-dependent intestinal epithelial cellmigration may be due partially to an increase of Kv1.1 channelexpression. The subsequent membrane hyperpolarization raisesCa2+]cyt by increasing the drivingforce (the electrochemical gradient) for Ca2+ influx andthus stimulates cell migration. |
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