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Research ArticleNeuropharmacology

Subunit-Specific Inhibition of Glycine Receptors by Curcumol

Li Wang, Wei-Guang Li, Chen Huang, Michael X. Zhu, Tian-Le Xu, Da-Zheng Wu and Yong Li
Journal of Pharmacology and Experimental Therapeutics November 2012, 343 (2) 371-379; DOI: https://doi.org/10.1124/jpet.112.195669
Li Wang
Institute of Chinese Materia Medica, Shanghai Key Laboratory of Complex Prescription, Shanghai University of Traditional Chinese Medicine, Shanghai, China (L.W., C.H., D.-Z.W.); Neuroscience Division, Department of Biochemistry and Molecular Cell Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China (W.-G.L., T.-L.X., Y.L.); and Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas (M.X.Z.)
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Wei-Guang Li
Institute of Chinese Materia Medica, Shanghai Key Laboratory of Complex Prescription, Shanghai University of Traditional Chinese Medicine, Shanghai, China (L.W., C.H., D.-Z.W.); Neuroscience Division, Department of Biochemistry and Molecular Cell Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China (W.-G.L., T.-L.X., Y.L.); and Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas (M.X.Z.)
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Chen Huang
Institute of Chinese Materia Medica, Shanghai Key Laboratory of Complex Prescription, Shanghai University of Traditional Chinese Medicine, Shanghai, China (L.W., C.H., D.-Z.W.); Neuroscience Division, Department of Biochemistry and Molecular Cell Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China (W.-G.L., T.-L.X., Y.L.); and Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas (M.X.Z.)
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Michael X. Zhu
Institute of Chinese Materia Medica, Shanghai Key Laboratory of Complex Prescription, Shanghai University of Traditional Chinese Medicine, Shanghai, China (L.W., C.H., D.-Z.W.); Neuroscience Division, Department of Biochemistry and Molecular Cell Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China (W.-G.L., T.-L.X., Y.L.); and Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas (M.X.Z.)
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Tian-Le Xu
Institute of Chinese Materia Medica, Shanghai Key Laboratory of Complex Prescription, Shanghai University of Traditional Chinese Medicine, Shanghai, China (L.W., C.H., D.-Z.W.); Neuroscience Division, Department of Biochemistry and Molecular Cell Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China (W.-G.L., T.-L.X., Y.L.); and Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas (M.X.Z.)
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Da-Zheng Wu
Institute of Chinese Materia Medica, Shanghai Key Laboratory of Complex Prescription, Shanghai University of Traditional Chinese Medicine, Shanghai, China (L.W., C.H., D.-Z.W.); Neuroscience Division, Department of Biochemistry and Molecular Cell Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China (W.-G.L., T.-L.X., Y.L.); and Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas (M.X.Z.)
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Yong Li
Institute of Chinese Materia Medica, Shanghai Key Laboratory of Complex Prescription, Shanghai University of Traditional Chinese Medicine, Shanghai, China (L.W., C.H., D.-Z.W.); Neuroscience Division, Department of Biochemistry and Molecular Cell Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China (W.-G.L., T.-L.X., Y.L.); and Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas (M.X.Z.)
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Abstract

Emerging evidence has suggested that inhibitory glycine receptors (GlyRs) are an important molecular target in the treatment of numerous neurological disorders. Rhizoma curcumae is a medicinal plant with positive neurological effects. In this study, we showed that curcumol, a major bioactive component of R. curcumae, reversibly and concentration-dependently inhibited the glycine-activated current (IGly) in cultured rat hippocampal neurons. The inhibitory effect was neither voltage- nor agonist concentration-dependent. Moreover, curcumol selectively inhibited homomeric α2-containing, but not α1- or α3-containing, GlyRs. The addition of β subunit conferred the curcumol sensitivity of α3-containing, but not α1-containing, GlyRs. Site-directed mutagenesis analysis revealed that a threonine at position 59 of the α2 subunit is critical for the susceptibility of GlyRs to curcumol-mediated inhibition. Furthermore, paralleling a decline of α2 subunit expression during spinal cord development, the degree of IGly inhibition by curcumol decreased with prolonged culture of rat spinal dorsal horn neurons. Taken together, our results suggest that the GlyRs are novel molecular targets of curcumol, which may underlie its pharmaceutical effects in the central nervous system.

Footnotes

  • This study was supported by the National Natural Science Foundation of China [Grants 91132303, 30970937]; the Shanghai Municipal Education Commission (Leading Academic Discipline Project J50201); the Shanghai Science and Technology Committee [Grant 09JC1408700]; and the China Postdoctoral Science Foundation [Grant 2012M511105].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.195669.

  • ABBREVIATIONS:

    GlyR
    glycine receptor
    IGly
    glycine-activated current
    CNS
    central nervous system
    SDH
    spinal dorsal horn
    CHO
    Chinese hamster ovary
    BMI
    bicuculline methiodide
    WT
    wild type
    DIV
    days in vitro
    GABAA
    γ-aminobutyric acid type A
    GABAAR
    A-type GABA receptor
    ICS 205-930
    1H-indole-3-carboxylic acid
    N.S.
    no significant difference.

  • Received April 17, 2012.
  • Accepted August 13, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 2
1 Nov 2012
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Research ArticleNeuropharmacology

The Inhibitory Effects of Curcumol on GlyRs

Li Wang, Wei-Guang Li, Chen Huang, Michael X. Zhu, Tian-Le Xu, Da-Zheng Wu and Yong Li
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 371-379; DOI: https://doi.org/10.1124/jpet.112.195669

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Research ArticleNeuropharmacology

The Inhibitory Effects of Curcumol on GlyRs

Li Wang, Wei-Guang Li, Chen Huang, Michael X. Zhu, Tian-Le Xu, Da-Zheng Wu and Yong Li
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 371-379; DOI: https://doi.org/10.1124/jpet.112.195669
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