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Potentiation of Surface Stability of AMPA Receptors by Sulfhydryl Compounds: A Redox-Independent Effect by Disrupting Palmitoylation

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Abstract

Sulfhydryl compounds such as dithiothreitol (DTT) and β-mercaptoethanol (β-ME) are widely used as redox agents. Previous studies in our group and other laboratory have reported the effect of sulfhydryl compounds on the function of glutamate receptor, including plasticity. Most of these findings have focused on the N-methyl-d-aspartic acid receptor, in contrast, very little is known about the effect of sulfhydryl compounds on α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR). Here, we observed that DTT (100 μM), β-ME (200 μM) and l-cysteine (200 μM) significantly elevated the surface expression of AMPARs via reducing their palmitoylation in rat hippocampal slices in vitro. Increased surface stability of AMPARs was not be correlated with the altered redox status, because the chemical entities containing mercapto group such as penicillamine (200 μM) and 2-mercapto-1-methylimidazole (200 μM) exhibited little effects on the surface expression of AMPARs. Computing results of Asp-His-His-Cys (DHHC) 3, the main enzyme for palmitoylation of AMPARs, indicated that only the alkyl mercaptans with chain-like configuration, such as DTT and β-ME, can enter the pocket of DHHC3 and disrupt the catalytic activity via inhibiting DHHC3 auto-palmitoylation. Collectively, our findings indicate a novel redox-independent mechanism underlay the multiple effects of thiol reductants on synaptic function.

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Abbreviations

ABE:

Acyl-biotin exchange

ACSF:

Artificial cerebrospinal fluid

AMPAR:

α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor

APV:

dl-2-amino-5-phosphonopentanoic acid

β-ME:

β-Mercaptoethanol

BS3 :

Bis (sulfosuccinymidal) suberate

CNS:

Central nervous system

CRD:

Cysteine-rich domain

DHHC:

Asp-His-His-Cys

DTT:

Dithiothreitol

HRP:

Horseradish peroxidase

LTP:

Long-term potentiation

MMTS:

Methylmethanethiosulfonate

NAC:

N-acetyl cysteine

NMDAR:

N-methyl-d-aspartic acid receptor

PATs:

Palmitoyl acyl transferases

PPTs:

Palmitoyl protein thioesterases

TTX:

Tetrodotoxin

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Acknowledgments

This work was supported by grants from the National Basic Research Program of China (the 973 Program, No. 2013CB531303 to Dr. J. G. C.; No. 2014CB744601 to F. W.) and the National Natural Scientific Foundation of China (NSFC, No. 81302754 to P. F. W; No. 81222048 to F. W.). It was also supported by the International Science & Technology Cooperation Program of China (No. 2011DFA32670) and PCSIRT (No. IRT13016) to J. G. C.

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Authors and Affiliations

  1. Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, China

    Jun Han, Hai Zhang, Jun Zhou, Yi Luo, Li-Hong Long, Zhuang-Li Hu, Fang Wang, Jian-Guo Chen & Peng-Fei Wu

  2. School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China

    Sheng Wang

  3. Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, 430030, Hubei, China

    Li-Hong Long, Zhuang-Li Hu, Fang Wang, Jian-Guo Chen & Peng-Fei Wu

  4. The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, Hubei, China

    Li-Hong Long, Zhuang-Li Hu, Fang Wang, Jian-Guo Chen & Peng-Fei Wu

  5. Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China

    Li-Hong Long, Zhuang-Li Hu, Fang Wang, Jian-Guo Chen & Peng-Fei Wu

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  1. Jun Han
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Correspondence to Peng-Fei Wu.

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Han, J., Zhang, H., Wang, S. et al. Potentiation of Surface Stability of AMPA Receptors by Sulfhydryl Compounds: A Redox-Independent Effect by Disrupting Palmitoylation. Neurochem Res 41, 2890–2903 (2016). https://doi.org/10.1007/s11064-016-2006-x

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