CAS Key Laboratory of Brain Function and Disease, and School of Life Sciences, University of Science and Technology of China, Hefei, PR China.
J Pharmacol Sci. 2012;119(2):177-85. doi: 10.1254/jphs.11183fp. Epub 2012 May 31.
In the present study, we investigated the effect of melatonin on the GABA-induced current (I(GABA) and GABAergic miniature inhibitory postsynaptic currents (mIPSCs) in cultured rat hippocampal neurons using the whole-cell patch-clamp technique. We found that melatonin rapidly and reversibly enhanced I(GABA) in a dose-dependent manner, with an EC50 of 949 μM. Melatonin markedly enhanced the peak amplitude of a subsaturating I(GABA) but not that of a saturating I(GABA). Interestingly, melatonin was effective only when GABA and melatonin were applied together. Furthermore, the effect of melatonin on I(GABA) was voltage-independent and did not change the ion selectivity of the GABA(A) receptor. The melatonin enhancement on I(GABA) can not be blocked by luzindole, a melatonin receptor antagonist, indicating that melatonin-induced I(GABA) enhancement was not via activation of its own membrane receptors. However, this enhancement may be mediated via high-affinity benzodiazepine sites as it was inhibited by the classical benzodiazepine antagonist flumazenil, suggesting an allosteric modulation of melatonin by binding to the sites of GABA(A) receptors. In addition, melatonin increased both amplitude and frequency of GABAergic mIPSCs, indicating that melatonin enhances GABAergic inhibitory transmission. Hence, our observation that melatonin has an enhancing effect on the GABAergic system may implicate a potential pathway for the neuroprotective effects of melatonin.
在本研究中，我们使用全细胞膜片钳技术研究了褪黑素对培养的大鼠海马神经元中 GABA 诱导电流（I(GABA)）和 GABA 能微小抑制性突触后电流（mIPSCs）的影响。我们发现褪黑素以剂量依赖的方式快速和可逆地增强 I(GABA)，EC50 为 949 μM。褪黑素明显增强了亚饱和 I(GABA)的峰值幅度，但不增强饱和 I(GABA)的峰值幅度。有趣的是，只有当 GABA 和褪黑素一起应用时，褪黑素才有效。此外，褪黑素对 I(GABA)的作用与电压无关，也不改变 GABA(A)受体的离子选择性。褪黑素对 I(GABA)的增强不能被 luzindole（褪黑素受体拮抗剂）阻断，表明褪黑素诱导的 I(GABA)增强不是通过激活其自身的膜受体。然而，这种增强可能是通过高亲和力苯二氮䓬位点介导的，因为它被经典的苯二氮䓬拮抗剂氟马西尼抑制，表明褪黑素通过与 GABA(A)受体的结合对其进行变构调节。此外，褪黑素增加了 GABA 能 mIPSCs 的幅度和频率，表明褪黑素增强了 GABA 能抑制性传递。因此，我们观察到褪黑素对 GABA 能系统具有增强作用，这可能暗示了褪黑素的神经保护作用的潜在途径。
