Sex and brain region ‐specific regulation of serotonin transporter activity in synaptosomes in guanine nucleotide‐binding protein G(q) alpha knockout mice

In this study, we show that the serotonin transporter (SERT) is sex specifically regulated by guanine nucleotide-binding protein alpha (G α)q. SERT-mediated uptake of 5-hydroxytryptamine (5HT) is enhanced in female Gαq knockout mice, which is correlated with differential Gαi1 expression in the midbrain, while in the frontal cortex the sexual dimorphism is caused by a down-regulation of SERT expression in male mice. The effects of G αq inhibitors, YM-254890 and BIM-46187, on SERT activity support the hypothesis that Gαq and Gαi, through direct interaction with SERT, inhibit 5HT uptake by modulating transport-associated conformational changes. AbstractThe regulation of the serotonin transporter (SERT) by guanine nucleotide-binding protein alpha (G α) q was investigated using Gαq knockout mice. In the absence of Gαq, SERT-mediated uptake of 5-hydroxytryptamine (5HT) was enhanced in midbrain and frontal cortex synaptosomes, but only in female mice. The mechanisms underlying this sexual dimorphism were investigated using quantitative western blot analysis revealing brain region-specific differences. In the frontal cortex, SERT protein expression was decreased in male knockout mice, seemingly explaining the sex-dependent variation in SERT activity. The differential expression of Gαi1 in female mice contributes to the sex differences in the midbrain. In fact, Gαi1 levels inversely correlate with 5HT uptake rates across both sexes and genotypes. Likely due to differential ...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research