Chronic antidepressant treatment effects on kinase gene expression patterns

The serotonin transporter, SERT, is a phosphoprotein whose function is determined by its phosphorylation state via multiple kinase pathways. At least two fundamental phosphorylation mechanisms may regulate SERT activity. Phosphorylation through protein kinases may serve both to regulate sequestration of SERT from the cell membrane, and also down-regulate SERT expression. Ligand occupancy has been recently shown to affect this system, with SSRIs blocking 5-HT's ability to inhibit phosphorylation-mediated sequestration of SERT. Consequently, the kinases may serve to regulate extracellular 5-HT concentrations with SERT upregulation in response to increased 5-HT, and down regulation of SERT in response to SSRIs. If this were true, then we might expect to see differences in protein kinase expression in response to SSRI treatment. To investigate this possibility, we studied 5 groups of rats 5 rats in each group (N = 25, males). Rats were assigned randomly to osmotic mini-pump treatment with placebo 3 days, placebo 21 days, fluoxetine 3 days, fluoxetine 21 days, or citalopram 21 days. Total RNA was isolated and labeled as cRNA, and incubated with Affymetrix gene chip and stained with Streptavidin-phycoerythrin conjugate, and read for changes in the kinase expression system as a result of antidepressant treatment. The results indicated that expression of several protein kinases increased with acute and decreased with chronic antidepressant treatment. The results are consistent with homeostasis of SERT function through a decrease in PK manufacture, in response to antidepressant treatment. The results suggest that gene variation in this system may underlie differences in response to antidepressant treatment since kinase down-regulation would counterbalance the SSRI effect, by lessening inhibition of SERT function, in response to treatment.