Neitz Angela, Mergia Evanthia, Imbrosci Barbara, Petrasch-Parwez Elisabeth, Eysel Ulf T, Koesling Doris, Mittmann Thomas
Institute of Physiology and Pathophysiology, University Medical Center of the Johannes-Gutenberg University, D-55128 Mainz, Germany and.
Department of Pharmacology and Toxicology.
Cereb Cortex. 2014 Jul;24(7):1923-36. doi: 10.1093/cercor/bht048. Epub 2013 Feb 28.
The nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling cascade participates in the modulation of synaptic transmission. The effects of NO are mediated by the NO-sensitive cGMP-forming guanylyl cyclases (NO-GCs), which exist in 2 isoforms with indistinguishable regulatory properties. The lack of long-term potentiation (LTP) in knock-out (KO) mice deficient in either one of the NO-GC isoforms indicates the contribution of both NO-GCs to LTP. Recently, we showed that the NO-GC1 isoform is located presynaptically in glutamatergic neurons and increases the glutamate release via hyperpolarization-activated cyclic nucleotide (HCN)-gated channels in the hippocampus. Electrophysiological analysis of hippocampal CA1 neurons in whole-cell recordings revealed a reduction of HCN currents and a hyperpolarizing shift of the activation curve in the NO-GC2 KOs associated with reduced resting membrane potentials. These features were mimicked in wild-type (WT) neurons with an NO-GC inhibitor. Analysis of glutamate receptors revealed a cGMP-dependent reduction of NMDA receptor currents in the NO-GC2 KO mice, which was mimicked in WT by HCN channel inhibition. Lowering extracellular Mg(2+) increased NMDA receptor currents in the NO-GC2 KO and allowed the induction of LTP that was absent at physiological Mg(2+). In sum, our data indicate that postsynaptic cGMP increases the N-methyl-D-aspartate (NMDA) receptor current by gating HCN channels and thereby is required for LTP.
一氧化氮（NO）/环磷酸鸟苷（cGMP）信号级联参与突触传递的调节。NO的作用由对NO敏感的生成cGMP的鸟苷酸环化酶（NO-GCs）介导，其存在两种具有难以区分的调节特性的亚型。缺乏任何一种NO-GC亚型的基因敲除（KO）小鼠中缺乏长时程增强（LTP），这表明两种NO-GCs对LTP均有贡献。最近，我们发现NO-GC1亚型位于海马体中谷氨酸能神经元的突触前，并通过超极化激活的环核苷酸（HCN）门控通道增加谷氨酸释放。全细胞记录中对海马CA1神经元的电生理分析显示，在与静息膜电位降低相关的NO-GC2基因敲除小鼠中，HCN电流减少且激活曲线发生超极化偏移。这些特征在使用NO-GC抑制剂的野生型（WT）神经元中也有体现。对谷氨酸受体的分析显示，在NO-GC2基因敲除小鼠中，NMDA受体电流出现cGMP依赖性降低，在野生型小鼠中通过抑制HCN通道也能模拟出这种情况。降低细胞外镁离子（Mg2+）浓度可增加NO-GC2基因敲除小鼠中的NMDA受体电流，并允许诱导出在生理镁离子浓度下不存在的LTP。总之，我们的数据表明，突触后的cGMP通过打开HCN通道增加N-甲基-D-天冬氨酸（NMDA）受体电流，因此是LTP所必需的。
