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J. Biol. Chem., Vol. 282, Issue 38, 28274-28284, September 21, 2007

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ERK1/2-p90^RSK-mediated Phosphorylation of Na⁺/H⁺ Exchanger Isoform 1

A ROLE IN ISCHEMIC NEURONAL DEATH^*

Jing Luo, Douglas B. Kintner, Gary E. Shull^¶, and Dandan Sun¹

From the Departments of Physiology and Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792 and the ^¶Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, Ohio 45267

The function and regulation of Na⁺/H⁺ exchanger isoform 1 (NHE1) following cerebral ischemia are not well understood. In this study, we demonstrate that extracellular signal-related kinases (ERK1/2) play a role in stimulation of neuronal NHE1 following in vitro ischemia. NHE1 activity was significantly increased during 10-60 min reoxygenation (REOX) after 2-h oxygen and glucose deprivation (OGD). OGD/REOX not only increased the V_max for NHE1 but also shifted the K_m toward decreased [H⁺]_i. These changes in NHE1 kinetics were absent when MAPK/ERK kinase (MEK) was inhibited by the MEK inhibitor U0126. There were no changes in the levels of phosphorylated ERK1/2 (p-ERK1/2) after 2 h OGD. The p-ERK1/2 level was significantly increased during 10-60 min REOX, which was accompanied by nuclear translocation. U0126 abolished REOX-induced elevation and translocation of p-ERK1/2. We further examined the ERK/90-kDa ribosomal S6 kinase (p90^RSK) signaling pathways. At 10 min REOX, phosphorylated NHE1 was increased with a concurrent elevation of phosphorylation of p90^RSK, a known NHE1 kinase. Inhibition of MEK activity with U0126 abolished phosphorylation of both NHE1 and p90^RSK. Moreover, neuroprotection was observed with U0126 or genetic ablation or pharmacological inhibition of NHE1 following OGD/REOX. Taken together, these results suggest that activation of ERK1/2-p90^RSK pathways following in vitro ischemia phosphorylates NHE1 and increases its activity, which subsequently contributes to neuronal damage.

Received for publication, March 20, 2007 , and in revised form, July 26, 2007.

^* This work was supported in part by National Institutes of Health Grant RO1NS48216 and American Heart Association Grant EIA 0540154 (to D. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Neurological Surgery, University of Wisconsin, H4/332 Clinical Sciences Center, 600 Highland Ave., Madison, WI 53792. Tel.: 608-263-4060; Fax: 608-263-1409; E-mail: sun{at}neurosurg.wisc.edu.

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