Osmotic shrinkage of human cervical cancer cells induces an extracellular Cl--dependent nonselective cation channel, which requires p38 MAPK

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Abstract

This study is to integrate a functional role of nonselective cation (NSC) channels into a model of volume regulation on osmotic shrinkage for human cervical cancer cells. Application of a hypertonic solution (400 mosM kg-1) induced cell shrinkage, which was accompanied by a 7-fold increase of inward currents at -80 mV from -4.1 ± 0.4 pA pF-1 to -29 ± 1.1 pA pF-1 (n = 36, p < 0.001). There is a good correlation of channel activity and cell volume changes. Replacement of bath Na+ by K+, Cs+, Li+, or Rb+ did not affect the stimulated inward current significantly, but replacement by Ca2+, Ba2+, or the impermeable cation N-methyl-D-glucamine abolished the inward current; this demonstrates that the shrinkage-induced currents discriminate poorly between monovalent cations but are not carried by divalent cations. Replacement of extracellular Cl- by gluconate abolished the shrinkage-induced currents in a concentration-dependent manner without changing the reversal potential. Gadolinium (Gd3+) inhibited the stimulated current, whereas bumetanide and amiloride had no inhibitory effect. Cell shrinkage triggered mitogen-activated protein (MAP) kinase cascades leading to the activation of MAP/extracellular signal-regulated kinase 1/2 (ERK1/2) kinase (MEK1/2), and p38 kinase. Interference with p38 MAPK by either the specific inhibitor (SB202190), or a dominant-negative mutant profoundly suppressed the activation of the shrinkage-induced NSC channels. In contrast, the regulatory mechanism of shrinkage-induced NSC channels was independent of the volume-responsive MEK1/2 signaling pathway. More importantly, the cell volume response to hypertonicity was inhibited significantly in p38 dominant-negative mutant or by SB202190. Therefore, p38 MAPK is critically involved in the activation of a shrinkage-induced NSC channel, which plays an important role in the volume regulation of human cervical cancer cells.

Original languageEnglish
Pages (from-to)45776-45784
Number of pages9
JournalJournal of Biological Chemistry
Volume277
Issue number48
DOIs
Publication statusPublished - 2002 Nov 29

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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