Calcineurin Interacts with the Serotonin Transporter C-Terminus to Modulate Its Plasma Membrane Expression and Serotonin Uptake - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Neuroscience Année : 2013

Calcineurin Interacts with the Serotonin Transporter C-Terminus to Modulate Its Plasma Membrane Expression and Serotonin Uptake

Résumé

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 posttranslational 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 Ca 2ϩ-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 ␤-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.
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hal-03030188 , version 1 (29-11-2020)

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Mathieu Seimandi, Pascal Seyer, C. Sehwan Park, Franck Vandermoere, Benjamin Chanrion, et al.. Calcineurin Interacts with the Serotonin Transporter C-Terminus to Modulate Its Plasma Membrane Expression and Serotonin Uptake. Journal of Neuroscience, 2013, 33 (41), pp.16189 - 16199. ⟨10.1523/jneurosci.0076-13.2013⟩. ⟨hal-03030188⟩
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