Serotonin increases ERK1/2 phosphorylation in astrocytes by stimulation of 5-HT2B and 5-HT2C receptors

Abstract

We have previously shown that fluoxetine causes ERK1/2 phosphorylation in cultured mouse astrocytes mediated exclusively by stimulation of 5-HT2B receptors (Li et al., 2008b). This raises the question whether this is also the case for serotonin (5-HT) itself. In the present study serotonin was found to induce ERK1/2 phosphorylation by stimulation of 5-HT2B receptors with high affinity (EC50: 20–30pM), and by stimulation of 5-HT2C receptor with low affinity (EC50: 1μM or higher). ERK1/2 phosphorylation induced by stimulation of either 5-HT2B or 5-HT2C receptors was mediated by epidermal growth factor (EGF) receptor transactivation (Peng et al., this issue), shown by the inhibitory effect of AG1478, an inhibitor of the EGF receptor tyrosine kinase, and GM6001, an inhibitor of Zn-dependent metalloproteinases, and thus of 5-HT2B receptor-mediated EGF receptor agonist release. It is discussed that the high potency of the 5-HT2B-mediated effect is consistent with literature data for binding affinity of serotonin to cloned human 5-HT2B receptors and with observations of low extracellular concentrations of serotonin in brain, which would allow a demonstrated moderate and modality-dependent increase in specific brain areas to activate 5-HT2B receptors. In contrast the relevance of the observed 5-HT2C receptors on astrocytes is questioned.