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. 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.
Mukhin
Yurii V
YV
Medical and Research Services of the Ralph H. Johnson Veterans Affairs Medical Center, Department of Medicine (Nephrology Division), Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA. mukhinyv@musc.edu
Garnovskaya
Maria N
MN
Ullian
Michael E
ME
Raymond
John R
JR
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D066246:ErbB Receptors / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000201:enzymology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology*
D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; D000804:Angiotensin II; D012701:Serotonin; D066246:ErbB Receptors; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases