Aim: The aim of this study was to determine the effect of long-term serotonin (5-hydroxytryptamine, 5-HT) treatment on the human serotonin transporter (hSERT) function and its expression.
Methods: This study was carried out in the enterocyte-like cell line Caco-2. These cells constitutively express the hSERT and have been shown to be an excellent model for the study of this protein. We measured serotonin transport, levels of mRNA expression and of the SERT protein after treating the cells with serotonin.
Results: Serotonin treatment diminished hSERT activity in a concentration and period-dependent way by increasing the K(t) value and reducing V(max). This inhibition was reversible and was not mediated by either the action of 5-HT(2), 5-HT(3) or 5-HT(4) receptors, or by the intracellular second messengers, protein kinase C and cAMP. 5-HT did not seem to affect either the mRNA level of the SERT or the protein transporter measured in either the membrane or the cell lysate. The 5-HT treatment effect was additive to the inhibitory effect of treatment with a low concentration of citalopram and fluoxetine. Nevertheless, 5-HT did not increase the inhibition yielded by treatment with high concentration citalopram.
Conclusion: The chronic increase in serotonin in the extracellular medium diminishes the function of the SERT. This effect seems to be due to an effect on the transporter molecule itself in the membrane, without altering protein synthesis, intracellular traffic, or its availability.