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- Title
The 5-HT transporter transactivates the PDGFβ receptor in pulmonary artery smooth muscle cells.
- Authors
Yinglin Liu; Min Li; Warburton, Rod R.; Hill, Nicholas S.; Fanburg, Barry L.
- 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 PDGFRβ through the 5-HTT in pulmonary artery (PA) SMCs. Inhibition of PDGFR kinase with imatinib or AG1296 blocks 5-HT-stimulated PDGFRβ phosphorylation. 5-HTT inhibitors and the Na+/K+-ATPase inhibitor ouabain, but not 5-HT2 and 5-HT1B/1D receptor inhibitors, block PDGFRβ activation by 5-HT. Notably, 5-HTT binds the PDGFRβ upon 5-HT stimulation and the 5-HTT inhibitor fluoxetine blocks both the binding and PDGDRβ activation. Activation of PDGFRβ may occur through oxidation of a catalytic cysteine of tyrosine phosphatase. 5-HT-activated PDGFRβ 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 PDGFRβ activation in mouse lung in vivo. In summary, these results demonstrate that 5-HT transactivates PDGFRβ in PASMCs leading to SMC proliferation and migration, and may be an important signaling pathway in the production of PH in vivo.
- Subjects
SEROTONIN; ACTIVE biological transport; PLATELET-derived growth factor; PULMONARY artery; SMOOTH muscle; OXIDATION
- Publication
FASEB Journal, 2007, Vol 21, Issue 11, p2725
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.06-8058com