Serotonin stimulates mitogen-activated protein kinase activity through the formation of superoxide anion.
Our previous studies have shown that, through an active transport process, serotonin (5-HT) rapidly elevates O(-)(2). formation, stimulates protein phosphorylation, and enhances proliferation of bovine pulmonary artery smooth muscle cells (SMCs). We presently show that 1 microM 5-HT also rapidly elevates phosphorylation and activation of the mitogen-activated protein (MAP) kinases extracellular signal-regulated kinase (ERK) 1 and ERK2 of SMCs, and the enhanced phosphorylation is blocked by the antioxidants Tiron, N-acetyl-L-cysteine (NAC), and Ginkgo biloba extract. Inhibition of MAP kinase with PD-98059 failed to block enhanced O(-)(2). formation by 5-HT. Chinese hamster lung fibroblasts (CCL-39 cells), which demonstrate both 5-HT transporter and receptor activity, showed a similar response to 5-HT (i.e., enhanced mitogenesis, O(-)(2). formation, and ERK1 and ERK2 phosphorylation and activation). Unlike SMCs, they also responded to 5-HT receptor agonists. We conclude that downstream signaling of MAP kinase is a generalized cellular response to 5-HT that occurs secondary to O(-)(2). formation and may be initiated by either the 5-HT transporter or receptor depending on the cell type.
Lee
S L
SL
Pulmonary and Critical Care Division, Department of Medicine, Tupper Research Institute, and New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Wang
W W
WW
Finlay
G A
GA
Fanburg
B L
BL
D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D002417:Cattle; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D020441:Ginkgo biloba / Q000737:chemistry; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology; D010946:Plants, Medicinal; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism*
D000975:Antioxidants; D010936:Plant Extracts; D013481:Superoxides; D012701:Serotonin; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000111:Acetylcysteine