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J. Biol. Chem., Vol. 279, Issue 3, 1845-1852, January 16, 2004

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ERK Is Regulated by Sodium-Proton Exchanger in Rat Aortic Vascular Smooth Muscle Cells^*

Yurii V. Mukhin, Maria N. Garnovskaya, Michael E. Ullian, and John R. Raymond

From the Medical and Research Services of the Ralph H. Johnson Veterans Affairs Medical Center and the Department of Medicine (Nephrology Division), Medical University of South Carolina, Charleston, South Carolina 29425

The purposes of this study were to test 1) the relationship between two widely studied mitogenic effector pathways, and 2) the hypothesis that sodium-proton exchanger type 1 (NHE-1) is a regulator of extracellular signal-regulated protein kinase (ERK) activation in rat aortic smooth muscle (RASM) cells. Angiotensin II (Ang II) and 5-hydroxytryptamine (5-HT) stimulated both ERK and NHE-1 activities, with activation of NHE-1 preceding that of ERK. The concentration-response curves for 5-HT and Ang II were superimposable for both processes. Inhibition of NHE-1 with pharmacological agents or by isotonic replacement of sodium in the perfusate with choline or tetramethylammonium greatly attenuated ERK activation by 5-HT or Ang II. Similar maneuvers significantly attenuated 5-HT- or Ang II-mediated activation of MEK and Ras but not transphosphorylation of the epidermal growth factor (EGF) receptor. EGF receptor blockade attenuated ERK activation, but not NHE-1 activation by 5-HT and Ang II, suggesting that the EGF receptor and NHE-1 work in parallel to stimulate ERK activity in RASM cells, converging distal to the EGF receptor but at or above the level of Ras in the Ras-MEK-ERK pathway. Receptor-independent activation of NHE-1 by acute acid loading of RASM cells resulted in the rapid phosphorylation of ERK, which could be blocked by pharmacological inhibitors of NHE-1 or by isotonic replacement of sodium, closely linking the proton transport function of NHE-1 to ERK activation. These studies identify NHE as a new regulator of ERK activity in RASM cells.

Received for publication, May 9, 2003 , and in revised form, October 20, 2003.

This work was supported by grants from the Department of Veterans Affairs (Merit Awards and a Research Enhancement Award program to M. N. G. and J. R. R.), the National Institutes of Health (DK52448 and DK52448-02 to J. R. R. and DK02694 to Y. V. M.), the American Heart Association (to M. E. U. and Y. V. M.), and a laboratory endowment jointly supported by the Medical University of South Carolina (MUSC) Division of Nephrology and Dialysis Clinics, Inc. (to M. E. U. and J. R. R.). The FLIPR is a shared MUSC resource obtained with Grant S10RR013005 from the United States Public Health Service. The microphysiometer is a shared Veterans Affairs resource obtained with a Veterans Affairs large-equipment grant. 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.

To whom correspondence should be addressed: Medical University of South Carolina, 96 Jonathan Lucas St., Rm. 829 CSB, P. O. Box 250623, Charleston, S.C. 29425-2227. Tel.: 843-789-6776 or 843-876-5128; Fax: 843-876-5129 or 843-792-8399; E-mail: mukhinyv{at}musc.edu.

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