Faculty Collaboration Database

ERK is regulated by sodium-proton exchanger in rat aortic vascular smooth muscle cells. J Biol Chem 2004 Jan 16;279(3):1845-52

Date

11/06/2003

Pubmed ID

14600156

DOI

10.1074/jbc.M304907200

Scopus ID

2-s2.0-0345826111 (requires institutional sign-in at Scopus site)   40 Citations

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.

Author List

Mukhin YV, Garnovskaya MN, Ullian ME, Raymond JR

Author

John R. Raymond MD President, CEO, Professor in the President department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Angiotensin II
Animals
ErbB Receptors
Hydrogen-Ion Concentration
Male
Mitogen-Activated Protein Kinases
Muscle, Smooth, Vascular
Myocytes, Smooth Muscle
Phosphorylation
Protein Kinase C
Rats
Rats, Sprague-Dawley
Serotonin
Sodium-Hydrogen Exchangers