Department of Neurophysiology, Institute of Physiology, Eberhard Karls University of Tübingen, 72074 Tübingen, Germany.
Int J Mol Sci. 2022 Jun 24;23(13):7048. doi: 10.3390/ijms23137048.
Cyclic guanosine monophosphate (cGMP) is a ubiquitous second messenger and a key molecule in many important signaling cascades in the body and brain, including phototransduction, olfaction, vasodilation, and functional hyperemia. Additionally, cGMP is involved in long-term potentiation (LTP), a cellular correlate of learning and memory, and recent studies have identified the cGMP-increasing drug Sildenafil as a potential risk modifier in Alzheimer's disease (AD). AD development is accompanied by a net increase in the expression of nitric oxide (NO) synthases but a decreased activity of soluble guanylate cyclases, so the exact sign and extent of AD-mediated imbalance remain unclear. Moreover, human patients and mouse models of the disease present with entangled deregulation of both cGMP and Ca signaling, e.g., causing changes in cGMP-mediated Ca release from the intracellular stores as well as Ca-mediated cGMP production. Still, the mechanisms governing such interplay are poorly understood. Here, we review the recent data on mechanisms underlying the brain cGMP signaling and its interconnection with Ca signaling. We also discuss the recent evidence stressing the importance of such interplay for normal brain function as well as in Alzheimer's disease.
环鸟苷酸（cGMP）是一种普遍存在的第二信使，也是体内和大脑中许多重要信号级联反应的关键分子，包括光转导、嗅觉、血管舒张和功能充血。此外，cGMP 还参与长时程增强（LTP），这是学习和记忆的细胞相关性，最近的研究已经确定 cGMP 增加药物西地那非（Sildenafil）是阿尔茨海默病（AD）的潜在风险调节剂。AD 的发展伴随着一氧化氮（NO）合酶表达的净增加，但可溶性鸟苷酸环化酶的活性降低，因此 AD 介导的失衡的确切迹象和程度仍不清楚。此外，该疾病的人类患者和小鼠模型表现出 cGMP 和 Ca 信号的纠缠失调，例如，导致细胞内储存的 cGMP 介导的 Ca 释放以及 Ca 介导的 cGMP 产生发生变化。尽管如此，控制这种相互作用的机制仍知之甚少。在这里，我们回顾了最近关于大脑 cGMP 信号转导及其与 Ca 信号转导相互连接的机制的研究数据。我们还讨论了最近的证据，强调了这种相互作用对于正常大脑功能以及阿尔茨海默病的重要性。
