Melatonin receptors limit dopamine reuptake by regulating dopamine transporter cell-surface exposure |
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| Authors: | Abla Benleulmi-Chaachoua Alan Hegron Marine Le Boulch Angeliki Karamitri Marta Wierzbicka Victoria Wong Igor Stagljar Philippe Delagrange Raise Ahmad Ralf Jockers |
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| Institution: | 1.Inserm, U1016, Institut Cochin,Paris,France;2.CNRS, UMR 8104,Paris,France;3.University of Paris Descartes, Sorbonne Paris Cité,Paris,France;4.Donnelly Centre, Department of Biochemistry, Faculty of Medicine,University of Toronto,Toronto,Canada;5.Department of Molecular Genetics, Faculty of Medicine,University of Toronto,Toronto,Canada;6.P?le d’Innovation Thérapeutique Neuropsychiatrie, Institut de Recherches Servier,Croissy,France |
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| Abstract: | Melatonin, a neuro-hormone released by the pineal gland, has multiple effects in the central nervous system including the regulation of dopamine (DA) levels, but how melatonin accomplishes this task is not clear. Here, we show that melatonin MT1 and MT2 receptors co-immunoprecipitate with the DA transporter (DAT) in mouse striatal synaptosomes. Increased DA re-uptake and decreased amphetamine-induced locomotor activity were observed in the striatum of mice with targeted deletion of MT1 or MT2 receptors. In vitro experiments confirmed the interactions and recapitulated the inhibitory effect of melatonin receptors on DA re-uptake. Melatonin receptors retained DAT in the endoplasmic reticulum in its immature non-glycosylated form. In conclusion, we reveal one of the first molecular complexes between G protein-coupled receptors (MT1 and MT2) and transporters (DAT) in which melatonin receptors regulate the availability of DAT at the plasma membrane, thus limiting the striatal DA re-uptake capacity in mice. |
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