Copyright © 2005, European Society of Cardiology
Role of SHP-1, Kv.1.2, and cGMP in nitric oxide-induced ERK1/2 MAP kinase dephosphorylation in rat vascular smooth muscle cells
aDepartment of Pharmacology, LSU Health Sciences Center at New Orleans, 1901 Perdido Street, New Orleans, LA 70112, United States
bDepartment of Physiology, LSU Health Sciences Center at New Orleans, 1901 Perdido Street, New Orleans, LA 70112, United States
* Corresponding author. Tel.: +1 504 568 2837; fax: +1 504 568 2361. Email address: kmatro{at}lsuhsc.edu
Objective: Nitric oxide (NO) elicits relaxation in vascular smooth muscle cells (VSMC) that is associated with guanylate cyclase (GC) and K+ channel activation. In this study we determined the mechanisms that lead to ERK1/2 MAP kinase dephosphorylation in response to NO.
Methods: VSMC were treated with the NO donor SNAP or sodium nitroprusside (SNP), and ERK1/2, Src homology (SH) 1 domain-containing protein tyrosine phosphatase (SHP-1), and Kv.1.2 phosphorylation were assessed by immunoprecipitation and Western blot analysis.
Results: NO decreased basal ERK1/2 phosphorylation in a dose- and time-dependent manner. NO-induced ERK1/2 dephosphorylation was detected at 1 min and sustained for 30 min. Pre-treatment with the GC inhibitor ODQ or the protein tyrosine phosphatase inhibitor I prevented ERK1/2 dephosphorylation induced by SNAP. The inhibition of protein phosphatase 1A/2A had no effect on ERK1/2 dephosphorylation induced by SNAP. Treatment with cromakalim A, a nonspecific K+ channel activator, also induced ERK1/2 dephosphorylation, while blockade of Kv.1.2 K+ channels (AM92016 hydrochloride) prevented NO-induced ERK1/2 dephosphorylation. In addition, SNAP induced SHP-1 phosphorylation, and the Kv.1.2 dephosphorylation increase and SHP-1 phosphorylation was blocked by ODQ or AM92016. The basal interaction between ERK1/2 and SHP-1 was decreased in response to SNAP stimulation. SHP-1 also interacted with Kv.1.2 under basal conditions and participates in Kv.1.2 activation. Using the mouse mesenteric resistance artery, we found that ERK1/2 MAP kinase is involved in regulation of myogenic tone.
Conclusion: Thus, our study provides the first evidence that NO controls basal ERK1/2 phosphorylation by a signaling cascade that involves a dynamic signaling complex between cGMP, Kv.1.2 and SHP-1.
KEYWORDS Nitric oxide; Tyrosine phosphatase SHP-1; Kv.1.2 potassium channel; cGMP; ERK1/2 MAP kinase; Relaxation
Time for primary review 21 days
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