Open AccessProtein Kinases Alter the Allosteric Modulation of the Serotonin Transporter In Vivo and In Vitro
Author(s) -
MnieFilali Ouissame,
Lau Thorsten,
Matthaeus Friederike,
Abrial Erika,
Delcourte Sarah,
El Mansari Mostafa,
Pershon Alan,
Schloss Patrick,
Sánchez Connie,
Haddjeri Nasser
Publication year - 2016
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.12562
Subject(s) - citalopram , staurosporine , serotonin transporter , escitalopram , pharmacology , allosteric regulation , serotonergic , protein kinase c , serotonin , protein kinase a , serotonin plasma membrane transport proteins , chemistry , kinase , protein kinase inhibitor , biology , antidepressant , biochemistry , endocrinology , receptor , hippocampus
Summary Aim Studies using S ‐ and R ‐enantiomers of the SSRI citalopram have shown that R ‐citalopram exerts an antagonistic effect on the efficacy of the antidepressant S ‐citalopram (escitalopram) through an interaction at an allosteric modulator site on the serotonin transporter ( SERT ). Here, we show that protein kinase signaling systems are involved in the allosteric modulation of the SERT in vivo and in vitro .Methods We assessed the effects of nonspecific protein kinase inhibitor staurosporine in the action of escitalopram and/or R ‐citalopram using electrophysiological and behavioral assays in rats and cell surface SERT expression measures in serotoninergic cells. Results Acute administration of R ‐citalopram counteracted the escitalopram‐induced suppression of the serotonin (5‐ HT ) neuronal firing activity and increase of the head twitches number following L‐5‐hydroxytryptophan injection. Importantly, these counteracting effects of R ‐citalopram were abolished by prior systemic administration of staurosporine. Interestingly, the preventing effect of staurosporine on 5‐ HT neuronal firing activity was abolished by direct activation of protein kinase C with phorbol 12‐myristate 13‐acetate. Finally, in vitro , quantification of the amount of cell surface‐expressed SERT molecules revealed that R ‐citalopram prevented escitalopram‐induced SERT internalization that was completely altered by staurosporine. Conclusion Taken together, these results highlight for the first time an involvement of protein kinases in the allosteric modulation of SERT function.