From membrane to nucleus: A three-wave hypothesis of cAMP signaling.
From membrane to nucleus: A three-wave hypothesis of cAMP signaling.
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DOI：
10.1016/j.jbc.2023.105497
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发表时间：
2024-01
影响因子：
4.8
通讯作者：
Altschuler, Daniel L
中科院分区：
文献类型：
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作者：
Pizzoni, Alejandro;Zhang, Xuefeng;Altschuler, Daniel L
几十年来，我们对 G 蛋白偶联受体 (GPCR) 活性和环 AMP (cAMP) 信号传导的了解仅限于质膜。然而，越来越多的证据通过引入内吞作用依赖性 GPCR 信号传导的概念来挑战这一观点。这种新兴的范式不仅强调 cAMP 的持续产生，而且强调其精确的亚细胞定位，从而改变了我们对该过程的时空组织的理解。从这个替代的角度出发，我们最近的工作揭示了内质网内吞作用依赖性钙释放在控制核 cAMP 水平中的作用。这是通过激活局部可溶性腺苷酸环化酶来实现的，该酶反过来又调节局部蛋白激酶 A (PKA) 的激活和下游转录事件。在这篇综述中，我们探讨了环 AMP 信号传导研究的动态演变，包括导致我们提出新的三波假说的发现。我们深入研究了如何放弃 cAMP 生成仅限于质膜的范式，以及对核 PKA 激活限速步骤的看法不断变化。
For many decades, our understanding of G protein-coupled receptor (GPCR) activity and cyclic AMP (cAMP) signaling was limited exclusively to the plasma membrane. However, a growing body of evidence has challenged this view by introducing the concept of endocytosis-dependent GPCR signaling. This emerging paradigm emphasizes not only the sustained production of cAMP but also its precise subcellular localization, thus transforming our understanding of the spatiotemporal organization of this process. Starting from this alternative point of view, our recent work sheds light on the role of an endocytosis-dependent calcium release from the endoplasmic reticulum in the control of nuclear cAMP levels. This is achieved through the activation of local soluble adenylyl cyclase, which in turn regulates the activation of local protein kinase A (PKA) and downstream transcriptional events. In this review, we explore the dynamic evolution of research on cyclic AMP signaling, including the findings that led us to formulate the novel three-wave hypothesis. We delve into how we abandoned the paradigm of cAMP generation limited to the plasma membrane and the changing perspectives on the rate-limiting step in nuclear PKA activation.