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.
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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