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J. Biol. Chem., Vol. 277, Issue 48, 45776-45784, November 29, 2002

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Osmotic Shrinkage of Human Cervical Cancer Cells Induces an Extracellular Cl-dependent Nonselective Cation Channel, Which Requires p38 MAPK^*

Meng-Ru Shen^§¶, Cheng-Yang Chou^§, Keng-Fu Hsu^§, and J. Clive Ellory^¶

From the  Department of Pharmacology, the ^§ Department of Obstetrics & Gynecology, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan and the ^¶ University Laboratory of Physiology, Parks Road, University of Oxford, OX1 3PT, United Kingdom

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 kg¹) induced cell shrinkage, which was accompanied by a 7-fold increase of inward currents at 80 mV from 4.1 ± 0.4 pA pF¹ to 29 ± 1.1 pA pF¹ (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.

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