Role of JNK in hypertonic activation of Cl--dependent Na+/H+ exchange in Xenopus oocytes

In the course of studying the hypertonicity-activated ion transporters in X enopus oocytes, we found that activation of endogenous oocyte Na+/H+ exchan ge activity (xoNHE) by hypertonic shrinkage required Cl-, with an EC50 for bath [Cl-] of similar to3 mM. This requirement for chloride was not support ed by several nonhalide anions and was not shared by xoNHE activated by aci d loading. Hypertonicity-activated xoNHE exhibited an unusual rank order of inhibitory potency among amiloride derivatives and was blocked by Cl- tran sport inhibitors. Chelation of intracellular Ca2+ by injection of EGTA bloc ked hypertonic activation of xoNHE, although many inhibitors of Ca2+-relate d signaling pathways were without inhibitory effect. Hypertonicity activate d oocyte extracellular signal-regulated kinase 1/2 (ERK1/2), but inhibitors of neither ERK1/2 nor p38 prevented hypertonic activation of xoNHE. Howeve r, hypertonicity also stimulated a Cl- dependent increase in c-Jun NH2-term inal kinase (JNK) activity. Inhibition of JNK activity prevented hypertonic activation of xoNHE but not activation by acid loading. We conclude that h ypertonic activation of Na+/H+ exchange in Xenopus oocytes requires Cl- and is mediated by activation of JNK.