RT Journal Article
SR Electronic
T1 Calcineurin Interacts with the Serotonin Transporter C-Terminus to Modulate Its Plasma Membrane Expression and Serotonin Uptake
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 16189
OP 16199
DO 10.1523/JNEUROSCI.0076-13.2013
VO 33
IS 41
A1 Mathieu Seimandi
A1 Pascal Seyer
A1 C. Sehwan Park
A1 Franck Vandermoere
A1 Benjamin Chanrion
A1 Joël Bockaert
A1 Isabelle M. Mansuy
A1 Philippe Marin
YR 2013
UL http://www.jneurosci.org/content/33/41/16189.abstract
AB Homeostasis of serotonergic transmission critically depends on the rate of serotonin reuptake via its plasma membrane transporter (SERT). SERT activity is tightly regulated by multiple mechanisms, including physical association with intracellular proteins and post-translational modifications, such as phosphorylation, but these mechanisms remain partially understood. Here, we show that SERT C-terminal domain recruits both the catalytic and regulatory subunits of the Ca2+-activated protein phosphatase calcineurin (CaN) and that the physical association of SERT with CaN is promoted by CaN activity. Coexpression of constitutively active CaN with SERT increases SERT cell surface expression and 5-HT uptake in HEK-293 cells. It also prevents the reduction of 5-HT uptake induced by an acute treatment of cells with the protein kinase C activator β-PMA and concomitantly decreases PMA-elicited SERT phosphorylation. In addition, constitutive activation of CaN in vivo favors 5-HT uptake in the adult mouse brain, whereas CaN inhibition reduces cerebral 5-HT uptake. Constitutive activation of CaN also decreases immobility in the forced swim test, indicative of an antidepressant-like effect of CaN. These results identify CaN as an important regulator of SERT activity in the adult brain and provide a novel molecular substrate of clinical interest for the understanding of increased risk of mood disorders in transplanted patients treated with immunosuppressive CaN inhibitors.