Multifaceted Regulations of the Serotonin Transporter: Impact on Antidepressant Response

Abstract

Serotonin transporter, SERT (SLC64A for solute carrier family 6, member A4), is a twelve transmembrane domain (TMDs) protein that assumes the uptake of serotonin (5-HT) through dissipation of the Na⁺ gradient established by the electrogenic pump Na/K ATPase. Abnormalities in 5-HT level and signaling have been associated with various disorders of the central nervous system (CNS) such as depression, obsessive-compulsive disorder, anxiety disorders, and autism spectrum disorder. Since the 50s, SERT has raised a lot of interest as being the target of a class of antidepressants, the Serotonin Selective Reuptake Inhibitors (SSRIs), used in clinics to combat depressive states. Because of the refractoriness of two-third of patients to SSRI treatment, a better understanding of the mechanisms regulating SERT functions is of priority. Here, we review how genetic and epigenetic regulations, post-translational modifications of SERT, and specific interactions between SERT and a set of diverse partners influence SERT expression, trafficking to and away from the plasma membrane and activity, in connection with the neuronal adaptive cell response to SSRI antidepressants.

Keywords: Na/K ATPase; SERT; SSRIs; microRNAs; phosphorylation; trafficking.

FIGURE 1

Schematic representation of SERT. SERT protein displays two N-linked glycosylation sites in the extracellular loop 2 (Launay et al., 1992; Tate and Blakely, 1994) and several sites of phosphorylation located in the N- and C-termini and in intracellular loops 1 and 2 (Vaughan, 2004; Sorensen et al., 2014).

FIGURE 2

Regulation of SERT function by the serotonergic receptor 5-HT_2B in 1C11^5-HT neuronal cells. At low 5-HT concentration, 5-HT_2BRs through its NO signaling coupling ensure a basal phosphorylation level of SERT, endowing it with an optimal 5-HT uptake activity. All SERT molecules are able to bind antidepressants. At high level of 5-HT, 5-HT_2BR-dependent protein kinase C (PKC) couplings provoke hyperphosphorylation of SERT that impairs its ability to uptake 5-HT. Under these conditions, only 1/3 of SERT molecules bind antidepressants.

FIGURE 3

miR-16, miR-15a, miR-135a, and miR-24 binding sites on the 3′ untranslated region of the SERT mRNA.

FIGURE 4

Central role of miR-16 in the adaptive response of neurons from raphe, locus coeruleus, and hippocampus to SSRI antidepressant treatment.