Serotonin stimulates mitogen-activated protein kinase activity through the formation of superoxide anion

Abstract

Our previous studies have shown that, through an active transport process, serotonin (5-HT) rapidly elevates[Formula: see text] formation, stimulates protein phosphorylation, and enhances proliferation of bovine pulmonary artery smooth muscle cells (SMCs). We presently show that 1 μM 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[Formula: see text] 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, [Formula: see text]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[Formula: see text] formation and may be initiated by either the 5-HT transporter or receptor depending on the cell type.

Exogenous Serotonin Regulates Proliferation of Interstitial Cells of Cajal in Mouse Jejunum Through 5-HT2B Receptors

“…63 This and the dose-dependent effects of the agonists 5-HT and BW 723C86 indicate that the compounds are producing a specific receptormediated increase in ICC number rather than having a nonspecific protective effect due to the known antioxidant activity of 5-HT and similar compounds. 64 The known expression of 5-HT 3 receptors on subsets of ICC and of 5-HT 4 receptors together with the data presented here that show expression of 5-HT 2B receptors on ICC suggest that 5-HT may have several modulatory effects on ICC. Additional experiments need to address the possible physiological role of endogenously released 5-HT on ICC.…”

Retinoids and Pulmonary Hypertension

“…Serotonin-induced smooth muscle cell proliferation has been shown to occur via ERK, 27 and we showed that ATRA partially inhibited phosphorylation of ERK induced by serotonin in human pulmonary artery smooth muscle cells. This indicates that ATRA, at least in part, exerts its growth-inhibitory effect via influencing the ERKdependent pathway.…”

“…Using serotonin to induce proliferation in human pulmonary artery smooth muscle cells, 27 we showed that ATRA completely blocked the increase in cell number. However, we cannot be certain that this finding has physiological relevance, because the concentration used approaches circulating levels seen in patients Figure 5.…”

“…27 In human pulmonary artery smooth muscle cells, serotonin rapidly and transiently phosphorylated ERK within 5 minutes, as determined by Western blot using a phospho-specific ERK antibody. ATRA caused partial inhibition of serotonin-induced ERK phosphorylation, whereas the specific MEK inhibitor PD98059 caused complete inhibition (Figure 3).…”

The Lbc Rho Guanine Nucleotide Exchange Factor/α-Catulin Axis Functions in Serotonin-induced Vascular Smooth Muscle Cell Mitogenesis and RhoA/ROCK Activation*

“…5-HT-induced PASMC mitogenesis requires RhoA/Rho kinase (ROCK) function (7), in addition to p42/44 ERK MAP kinase (8) and AKT pathways (9). RhoA mediates multiple cellular responses such as cell shape changes, contractility, migration, gene transcription, and growth via a distinct signaling pathway that regulates actomyosin filament assembly, serum response factor (SRF)-dependent gene transcription, and cell cycle progression (10).…”