Abstract
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.
Highlights
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
Receptor-independent activation of Naϩ/Hϩ exchangers (NHE)-1 by acute acid loading of rat aortic vascular smooth muscle (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
We have recently shown that the 5-HT2A and AT1A receptors activate NHE in RASM cells through a protein kinase C (PKC)-independent pathway that involves phospholipase C, elevated intracellular Ca2ϩ, CaM, and Janus kinase 2 [38]
Summary
Vol 279, No 3, Issue of January 16, pp. 1845–1852, 2004 Printed in U.S.A. ERK Is Regulated by Sodium-Proton Exchanger in Rat Aortic Vascular Smooth Muscle Cells*. 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. Recent work has shown that short-term activation of ERK leads to rapid stimulation of NHE-1 in multiple cell types (platelets, erythrocytes, fibroblasts, MDCK-11 cells, rabbit skeletal muscle, and cultured rat neonatal and adult ventricular cardiomyocytes) when activated by diverse stimuli, including angiotensin II (Ang II), cannabinoid ligands, aldosterone, and H2O2 (10 –22). Subsequent protein kinase; Ang II, angiotensin II; BCECF, 2Ј-7Ј-bis[2-carboxymethyl]-5[6]-carboxyfluorescein; CaM, calmodulin; EGF, epidermal growth factor; ECAR, extracellular acidification rate; EIPA, 5-N-ethylN-isopropyl-amiloride; FLIPR, fluorescent imaging plate reader; 5-HT, 5-hydroxytryptamine; MEK, mitogen- and extracellular signal-regulated kinase kinase; MIA, 5-N-methyl-N-isobutyl-amiloride; NHE, Naϩ/Hϩ exchanger; NHE-1, type 1 NHE; PKC, protein kinase C; PMA, phorbol 12-myristate 13-acetate; RASM, rat aortic smooth muscle cells. In the current study we investigated the role of NHE in ERK activation in vascular smooth muscle cells derived from rat aorta using 5-HT and Ang II as our primary test agents
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