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Calcineurin interacts with the serotonin transporter C-terminus to modulate its plasma membrane expression and serotonin uptake


Seimandi, Mathieu; Seyer, Pascal; Park, C Sehwan; Vandermoere, Franck; Chanrion, Benjamin; Bockaert, Joël; Mansuy, Isabelle M; Marin, Philippe (2013). Calcineurin interacts with the serotonin transporter C-terminus to modulate its plasma membrane expression and serotonin uptake. Journal of Neuroscience, 33(41):16189-16199.

Abstract

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 Ca(2+)-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.

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 Ca(2+)-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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > The KEY Institute for Brain-Mind Research
04 Faculty of Medicine > Brain Research Institute
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:9 October 2013
Deposited On:28 Nov 2013 14:36
Last Modified:05 Apr 2016 17:12
Publisher:Society for Neuroscience
ISSN:0270-6474
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1523/JNEUROSCI.0076-13.2013
PubMed ID:24107951
Permanent URL: https://doi.org/10.5167/uzh-85638

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