Institute of Pharmacology and Toxicology, Ruhr-University Bochum, Bochum, Germany.
Eur J Neurosci. 2022 Jan;55(1):18-31. doi: 10.1111/ejn.15564. Epub 2021 Dec 22.
In the central nervous system, the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signalling cascade has an established role in fine-tuning of synaptic transmission. In the present study, we asked which isoform of NO-sensitive guanylyl cyclase, NO-GC1 or NO-GC2, is responsible for generation of N-methyl-d-aspartate (NMDA)- and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-induced cGMP signals and which of the phosphodiesterases (PDEs) is responsible for degradation. To this end, we performed live cell fluorescence measurements of primary hippocampal neurons isolated from NO-GC isoform-deficient mice. Although both isoforms contributed to the NMDA- and AMPA-induced cGMP signals, NO-GC2 clearly played the predominant role. Whereas under PDE-inhibiting conditions the cGMP levels elicited by both glutamatergic ligands were comparable, NMDA-induced cGMP signals were clearly higher than the AMPA-induced ones in the absence of PDE inhibitors. Thus, AMPA-induced cGMP signals are more tightly controlled by PDE-mediated degradation than NMDA-induced signals. In addition, these findings are compatible with the existence of at least two different pools of cGMP in both of which PDE1 and PDE2-known to be highly expressed in the hippocampus-are mainly responsible for cGMP degradation. The finding that distinct pools of cGMP are equipped with different amounts of PDEs highlights the importance of PDEs for the shape of NO-induced cGMP signals in the central nervous system.
在中枢神经系统中，一氧化氮（NO）/环鸟苷酸（cGMP）信号级联在微调突触传递方面起着重要作用。在本研究中，我们想知道哪种 NO 敏感型鸟苷酸环化酶同工型，NO-GC1 或 NO-GC2，负责产生 N-甲基-D-天冬氨酸（NMDA）和 AMPA（α-氨基-3-羟基-5-甲基-4-异恶唑丙酸）诱导的 cGMP 信号，以及哪种磷酸二酯酶（PDEs）负责降解。为此，我们对来自 NO-GC 同工型缺陷小鼠的原代海马神经元进行了活细胞荧光测量。尽管两种同工型都有助于 NMDA 和 AMPA 诱导的 cGMP 信号，但 NO-GC2 显然起主要作用。虽然在 PDE 抑制条件下，两种谷氨酸能配体诱导的 cGMP 水平相当，但在没有 PDE 抑制剂的情况下，NMDA 诱导的 cGMP 信号明显高于 AMPA 诱导的信号。因此，与 NMDA 诱导的 cGMP 信号相比，AMPA 诱导的 cGMP 信号受到 PDE 介导的降解的更严格控制。此外，这些发现与至少存在两种不同的 cGMP 池的存在是一致的，其中 PDE1 和 PDE2-已知在海马体中高度表达-主要负责 cGMP 的降解。不同的 cGMP 池配备了不同数量的 PDEs 的发现强调了 PDEs 对中枢神经系统中 NO 诱导的 cGMP 信号形状的重要性。
