Subunit-specific inhibition of glycine receptors by curcumol.
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.
Institute of Chinese Materia Medica, Shanghai Key Laboratory of Complex Prescription, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Li
L
Wang
Wei-Guang
WG
Li
Chen
C
Huang
Michael X
MX
Zhu
Tian-Le
TL
Xu
Da-Zheng
DZ
Wu
Yong
Y
Li
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects; D030024:Curcuma / Q000737:chemistry; D003627:Data Interpretation, Statistical; D055724:Electrophysiological Phenomena; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D008516:Medicine, Chinese Traditional; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D018408:Patch-Clamp Techniques; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D011994:Recombinant Proteins; D012717:Sesquiterpenes / Q000494:pharmacology*; D013912:Threonine / Q000737:chemistry
C501174:Glra2 protein, rat; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D011994:Recombinant Proteins; D012717:Sesquiterpenes; D013912:Threonine; C022801:curcumol