Papke Roger L, Peng Can, Kumar Ashok, Stokes Clare
Department of Pharmacology and Therapeutics, University of Florida, PO Box 100267, Gainesville, FL 32610, United States.
Department of Pharmacology and Therapeutics, University of Florida, PO Box 100267, Gainesville, FL 32610, United States.
Neurosci Lett. 2018 Jun 11;677:6-13. doi: 10.1016/j.neulet.2018.04.025. Epub 2018 Apr 19.
Long-term potentiation (LTP) in the dentate gyrus was previously shown to be enhanced by nicotine, an effect dependent on both homomeric α7 and heteromeric α2β2 nicotinic acetylcholine receptors (nAChR). In our experiments, bath-applied nicotine produced no significant enhancement of LTP. The α7 nAChR silent agonist NS6740, a weak activator of α7 nAChR ion channels but an effective modulator of the cholinergic anti-inflammatory pathway, decreased LTP and, additionally, produced a substantial reduction in the baseline synaptic function prior to the high frequency stimulation used to induce LTP. The effects of NS6740 on the various ligand-gated ion channels associated with the generation and modulation of dentate LTP were evaluated with receptors expressed in Xenopus oocytes. A 60 s pre-application of 5 μM NS6740 to α7 receptors blocked the response to subsequent applications of acetylcholine (ACh). In contrast, the responses of α2β2 nAChR to control applications of ACh were not significantly affected by NS6740. Likewise, responses of cells expressing GluR1 + GluR2 AMPA-type glutamate receptor subunits or GABA α1, β2, and γ2L subunits to control agonist applications (100 μM kainic acid or 10 μM GABA, respectively), were unaffected by NS6740. The effects of NS6740 on α7 were inconsistent with simple antagonism since, while unresponsive to ACh, the receptors exposed to NS6740 were effectively activated by the positive allosteric modulator PNU-120596. The results support the hypothesis that NS6740 switches the mode of α7 signaling in a channel-independent manner that can reduce synaptic function.
先前的研究表明，尼古丁可增强齿状回中的长时程增强（LTP），这一效应依赖于同聚体α7和异聚体α2β2烟碱型乙酰胆碱受体（nAChR）。在我们的实验中，浴加尼古丁并未显著增强LTP。α7 nAChR沉默激动剂NS6740是α7 nAChR离子通道的弱激活剂，但却是胆碱能抗炎途径的有效调节剂，它可降低LTP，此外，在用于诱导LTP的高频刺激之前，还会使基线突触功能大幅降低。利用非洲爪蟾卵母细胞中表达的受体，评估了NS6740对与齿状回LTP的产生和调节相关的各种配体门控离子通道的影响。对α7受体预先施加5 μM NS6740 60秒，可阻断其对随后施加的乙酰胆碱（ACh）的反应。相比之下，NS6740对α2β2 nAChR对ACh对照应用的反应没有显著影响。同样，表达GluR1 + GluR2 AMPA型谷氨酸受体亚基或GABA α1、β2和γ2L亚基的细胞对对照激动剂应用（分别为100 μM海藻酸或10 μM GABA）的反应也不受NS6740影响。NS6740对α7的作用与简单拮抗作用不一致，因为虽然对ACh无反应，但暴露于NS6740的受体可被正变构调节剂PNU-120596有效激活。这些结果支持了这样一种假说，即NS6740以一种不依赖通道的方式切换α7信号传导模式，从而降低突触功能。
