1. Valproic Acid Influences MTNR1A Intracellular Trafficking and Signaling in a β-Arrestin 2-Dependent Manner.
- Author
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Hong LJ, Jiang Q, Long S, Wang H, Zhang LD, Tian Y, Wang CK, Cao JJ, Tao RR, Huang JY, Liao MH, Lu YM, Fukunaga K, Zhou NM, and Han F
- Subjects
- Animals, Cyclic AMP-Dependent Protein Kinases metabolism, Endocytosis drug effects, Extracellular Signal-Regulated MAP Kinases metabolism, Fluorescence Resonance Energy Transfer, HEK293 Cells, Humans, Melatonin pharmacology, Mice, Phosphorylation drug effects, Protein Binding drug effects, Protein Transport drug effects, rab GTP-Binding Proteins metabolism, Intracellular Space metabolism, Receptor, Melatonin, MT1 metabolism, Signal Transduction drug effects, Valproic Acid pharmacology, beta-Arrestins metabolism
- Abstract
Valproate exposure is associated with increased risks of autism spectrum disorder. To date, the mechanistic details of disturbance of melatonin receptor subtype 1 (MTNR1A) internalization upon valproate exposure remain elusive. By expressing epitope-tagged receptors (MTNR1A-EGFP) in HEK-293 and Neuro-2a cells, we recorded the dynamic changes of MTNR1A intracellular trafficking after melatonin treatment. Using time-lapse confocal microscopy, we showed in living cells that valproic acid interfered with the internalization kinetics of MTNR1A in the presence of melatonin. This attenuating effect was associated with a decrease in the phosphorylation of PKA (Thr197) and ERK (Thr202/Tyr204). VPA treatment did not alter the whole-cell currents of cells with or without melatonin. Furthermore, fluorescence resonance energy transfer imaging data demonstrated that valproic acid reduced the melatonin-initiated association between YFP-labeled β-arrestin 2 and CFP-labeled MTNR1A. Together, we suggest that valproic acid influences MTNR1A intracellular trafficking and signaling in a β-arrestin 2-dependent manner.
- Published
- 2016
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