Institute of Chinese Materia Medica, Shanghai Key Laboratory of Complex Prescription, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
J Pharmacol Exp Ther. 2012 Nov;343(2):371-9. doi: 10.1124/jpet.112.195669. Epub 2012 Aug 14.
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.
新出现的证据表明，抑制性甘氨酸受体（GlyRs）是治疗多种神经疾病的重要分子靶点。姜黄是一种具有积极神经作用的药用植物。在这项研究中，我们表明姜黄素，姜黄的主要生物活性成分，可在培养的大鼠海马神经元中可逆且浓度依赖性地抑制甘氨酸激活的电流（IGly）。抑制作用既不是电压依赖性的，也不是激动剂浓度依赖性的。此外，姜黄素选择性抑制同型 α2 亚基组成的 GlyRs，而不抑制 α1 或 α3 亚基组成的 GlyRs。β亚基的添加赋予了 α3 亚基组成的 GlyRs 对姜黄素的敏感性，但不赋予 α1 亚基组成的 GlyRs 的敏感性。定点突变分析表明，α2 亚基位置 59 的苏氨酸对于 GlyRs 对姜黄素介导的抑制作用的敏感性至关重要。此外，与脊髓发育过程中 α2 亚基表达下降平行，姜黄素对 IGly 的抑制程度随着大鼠脊髓背角神经元培养时间的延长而降低。总之，我们的结果表明 GlyRs 是姜黄素的新型分子靶点，这可能是其在中枢神经系统中的药物作用的基础。
