Cyclic GMP‐Dependent Protein Kinase and Cellular Signaling in the Nervous System
Cyclic GMP‐Dependent Protein Kinase and Cellular Signaling in the Nervous System
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DOI：
10.1046/j.1471-4159.1997.68020443.x
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发表时间：
1997-02
影响因子：
4.7
通讯作者：
Xin Wang;P. Robinson
中科院分区：
文献类型：
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作者：
Xin Wang;P. Robinson
摘要：一氧化氮（NO）和利钠肽激素在许多神经元功能（包括学习和记忆）中发挥着关键作用。大多数数据表明，它们通过激活可溶性和颗粒鸟苷酸环化酶来提高细胞内环鸟苷酸 (cGMP) 水平，从而发挥聚合作用。然而，cGMP 只是多个信号级联的起点，目前正在开始定义这些级联。 cGMP 水平升高的主要作用是刺激 cGMP 依赖性蛋白激酶 (PKG)，它是 cGMP 的主要细胞内受体蛋白，可磷酸化底物蛋白以发挥其作用。人们越来越清楚 PKG 介导 cGMP 的一些神经元效应，但其具体机制尚不清楚。在纹状体黑质神经末梢中已经报道了这一通路的清晰例证，其中 NO 通过 PKG 介导蛋白磷酸酶调节剂多巴胺和环 AMP 调节的磷蛋白的磷酸化，其分子量为 32,000 (DARPP-32)。大脑中已知身份的 PKG 底物非常少。对这些蛋白质以及神经系统中可能存在的其他组织中已知的蛋白质的调查揭示了 cGMP 和 PKG 信号可能调节神经功能的关键分子位点。这些潜在的底物通过调节蛋白质磷酸酶、细胞内钙水平以及许多离子通道和神经递质受体的功能，对蛋白质磷酸化网络产生深远的影响。大脑还含有丰富多样的特定 PKG 底物，其身份尚不清楚。他们未来的鉴定将提供令人兴奋的新线索，使人们能够更好地了解 PKG 信号在大脑功能的基本和高级功能中的作用。
Abstract: Nitric oxide (NO) and natriuretic peptide hormones play key roles in a surprising number of neuronal functions, including learning and memory. Most data suggest that they exert converging actions by elevation of intracellular cyclic GMP (cGMP) levels through activation of soluble and particulate guanylyl cyclases. However, cGMP is only the starting point for multiple signaling cascades, which are now beginning to be defined. A primary action of elevated cGMP levels is the stimulation of cGMP‐dependent protein kinase (PKG), the major intracellular receptor protein for cGMP, which phosphorylates substrate proteins to exert its actions. It has become increasingly clear that PKG mediates some of the neuronal effects of cGMP, but how is not yet clear. One clear illustration of this pathway has been reported in striatonigral nerve terminals, where NO mediates phosphorylation of the protein phosphatase regulator dopamine‐ and cyclic AMP‐regulated phosphoprotein having a molecular mass of 32,000 (DARPP‐32) by PKG. There are remarkably few PKG substrates in brain whose identities are known. A survey of these proteins and those known from other tissues that might also be found in the nervous system reveals the key molecular sites where cGMP and PKG signaling is likely to be regulating neural function. These potential substrates are critically placed to have profound effects on the protein phosphorylation network through regulation of protein phosphatases, intracellular calcium levels, and the function of many ion channels and neurotransmitter receptors. The brain also contains a rich diversity of specific PKG substrates whose identities are not yet known. Their future identification will provide exciting new leads that will permit better understanding of the role of PKG signaling in both basic and higher orders of brain function.