The 5-ht Transporter Transactivates the Pdgfbeta Receptor in Pulmonary Artery Smooth Muscle Cells.
From: Pulmonary, Critical Care and Sleep Division, Tufts-New England Medical Center, 750 Washington St., Boston, MA 02111, USA.
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publish Date: Sep 2007
- ISSN: 1530-6860
- Volume: 21
- Issue: 11
- Pages: 2725-34
- Medium: Internet
- Language: English
- Citation (JAMA): Liu Yinglin, Li Min, Warburton Rod R, et al. The 5-ht Transporter Transactivates the Pdgfbeta Receptor in Pulmonary Artery Smooth Muscle Cells.. FASEB J. Sep 2007;21:2725-34
Abstract
Serotonin (5-HT) stimulates smooth muscle cell growth through 5-HT receptors and the 5-HT transporter (5-HTT), and has been associated with pulmonary hypertension (PH). Platelet-derived growth factor receptors (PDGFR) have also been associated with PH. We present evidence for the first time that 5-HT transactivates PDGFRbeta through the 5-HTT in pulmonary artery (PA) SMCs. Inhibition of PDGFR kinase with imatinib or AG1296 blocks 5-HT-stimulated PDGFRbeta phosphorylation. 5-HTT inhibitors and the Na+/K+-ATPase inhibitor ouabain, but not 5-HT2 and 5-HT1B/1D receptor inhibitors, block PDGFRbeta activation by 5-HT. Notably, 5-HTT binds the PDGFRbeta upon 5-HT stimulation and the 5-HTT inhibitor fluoxetine blocks both the binding and PDGDRbeta activation. Activation of PDGFRbeta may occur through oxidation of a catalytic cysteine of tyrosine phosphatase. 5-HT-activated PDGFRbeta phosphorylation is blocked by the antioxidant N-acetyl-L-cysteine and the NADPH oxidase inhibitor, DPI. Inhibition of PDGFR kinase with imatinib or AG1296 significantly inhibits SMC proliferation and migration induced by 5-HT in vitro. Infusion of 5-HT by miniosmotic pumps enhances PDGFRbeta activation in mouse lung in vivo. In summary, these results demonstrate that 5-HT transactivates PDGFRbeta in PASMCs leading to SMC proliferation and migration, and may be an important signaling pathway in the production of PH in vivo.
Mesh Headings (Keywords): Animals, Antioxidants, Blotting, Western, Cell Movement, Cell Proliferation, Immunoprecipitation, Lung, Mice, Muscle, Smooth, Vascular, Phosphorylation, Protein Tyrosine Phosphatases, Pulmonary Artery, Reactive Oxygen Species, Receptor, Platelet-Derived Growth Factor beta, Serotonin, Serotonin Plasma Membrane Transport Proteins, Signal Transduction, Thiazolidines, Trans-Activation (Genetics), Tyrosine, Wound Healing
Check for Full Text / PubMed Unique Identifier (PMID): 17504974
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