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Valproic Acid Influences MTNR1A Intracellular Trafficking and Signaling in a β-Arrestin 2-Dependent Manner

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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.

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Abbreviations

VPA:

2-Propylpentanoic acid

MTNR1A:

Melatonin receptor subtype 1

PKA:

Protein kinase A

PKC:

Protein kinase C

FRET:

Fluorescence resonance energy transfer

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Acknowledgments

This work was supported by the National Natural Science Foundations of China (81402908, 81403024), Foundations of Hangzhou City Science and Technology Project (20130633B01), Foundations of Zhejiang Pharmaceutical Society (2013ZYY39), and Zhejiang Provincial Natural Science Foundation of China (LQ13H310001).

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The authors declare no conflicts of interest.

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    Authors and Affiliations

    1. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

      Ling-juan Hong, Quan Jiang, Sen Long, Huan Wang, Ling-di Zhang, Yun Tian, Cheng-kun Wang, Jing-jing Cao, Rong-rong Tao, Ji-yun Huang, Mei-hua Liao & Feng Han

    2. Department of Pharmacy, Hangzhou No.7 People’s Hospital, Hangzhou, China

      Sen Long

    3. Department of Pharmacy, Zhejiang Xiaoshan Hospital, Hangzhou, Zhejiang, China

      Ling-di Zhang

    4. School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang, China

      Ying-mei Lu

    5. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan

      Kohji Fukunaga

    6. Institute of Biochemistry, College Life Science, Zhejiang University, Hangzhou, China

      Nai-ming Zhou

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    1. Ling-juan Hong
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    Ling-juan Hong and Quan Jiang contributed equally to this work.

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    Hong, Lj., Jiang, Q., Long, S. et al. Valproic Acid Influences MTNR1A Intracellular Trafficking and Signaling in a β-Arrestin 2-Dependent Manner. Mol Neurobiol 53, 1237–1246 (2016). https://doi.org/10.1007/s12035-014-9085-y

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