title: Potentiation of Surface Stability of AMPA Receptors by Sulfhydryl Compounds: A Redox-Independent Effect by Disrupting Palmitoylation.
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.
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Zhang
authors.affiliation: School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, China.|Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, 430030, Hubei, China.|The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, Hubei, China.|Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
authors.forename: Li-Hong
authors.initials: LH
authors.lastname: Long
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, China.|Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, 430030, Hubei, China.|The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, Hubei, China.|Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
authors.forename: Zhuang-Li
authors.initials: ZL
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, China.|Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, 430030, Hubei, China.|The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, Hubei, China.|Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, China.|Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, 430030, Hubei, China.|The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, Hubei, China.|Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, China. wupengfeipharm@foxmail.com.|Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, 430030, Hubei, China. wupengfeipharm@foxmail.com.|The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, Hubei, China. wupengfeipharm@foxmail.com.|Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China. wupengfeipharm@foxmail.com.
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Wu
mesh_terms: D000818:Animals; D003545:Cysteine / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D054878:Lipoylation / Q000502:physiology; D008297:Male; D016202:N-Methylaspartate / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D013438:Sulfhydryl Compounds; D016202:N-Methylaspartate; D003545:Cysteine
keywords: DHHC (Asp-His-His-Cys) 3; GluA1; GluA2; Mercaptan; Palmitoylation; α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR)