Inhibition of K_v channel expression by NSAIDs depolarizes membrane potential and inhibits cell migration by disrupting calpain signaling

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• 作者：Kristopher Silver ; ^{ksilver@ksu.edu" class="auth_mail" title="E-mail the corresponding author} ; Alaina Littlejohn ; Laurel Thomas ; Elizabeth Marsh ; James D. Lillich
• 关键词：Indomethacin (PubChem CID ; 3715) ; NS-398 (PubChem CID ; 4553) ; SC-560 (PubChem CID ; 4306515)
• 刊名：Biochemical Pharmacology
• 出版年：2015
• 出版时间：15 December 2015
• 年：2015
• 卷：98
• 期：4
• 页码：614-628
• 全文大小：3545 K

文摘

Clinical use of non-steroidal anti-inflammatory drugs (NSAIDs) is well known to cause gastrointestinal ulcer formation via several mechanisms that include inhibiting epithelial cell migration and mucosal restitution. The drug-affected signaling pathways that contribute to inhibition of migration by NSAIDs are poorly understood, though previous studies have shown that NSAIDs depolarize membrane potential and suppress expression of calpain proteases and voltage-gated potassium (K_v) channel subunits. K_v channels play significant roles in cell migration and are targets of NSAID activity in white blood cells, but the specific functional effects of NSAID-induced changes in K_v channel expression, particularly on cell migration, are unknown in intestinal epithelial cells. Accordingly, we investigated the effects of NSAIDs on expression of K_v1.3, 1.4, and 1.6 in vitro and/or in vivo and evaluated the functional significance of loss of K_v subunit expression. Indomethacin or NS-398 reduced total and plasma membrane protein expression of K_v1.3 in cultured intestinal epithelial cells (IEC-6). Additionally, depolarization of membrane potential with margatoxin (MgTx), 40 mM K⁺, or silencing of K_v channel expression with siRNA significantly reduced IEC-6 cell migration and disrupted calpain activity. Furthermore, in rat small intestinal epithelia, indomethacin and NS-398 had significant, yet distinct, effects on gene and protein expression of K_v1.3, 1.4, or 1.6, suggesting that these may be clinically relevant targets. Our results show that inhibition of epithelial cell migration by NSAIDs is associated with decreased expression of K_v channel subunits, and provide a mechanism through which NSAIDs inhibit cell migration and may contribute to NSAID-induced gastrointestinal (GI) toxicity.