The interplay of multiple molecular and cellular components is necessary for compartmentalization of cAMP. Focus on "Assessment of cellular mechanisms contributing to cAMP compartmentalization in pulmonary microvascular endothelial cells".
The interplay of multiple molecular and cellular components is necessary for compartmentalization of cAMP. Focus on "Assessment of cellular mechanisms contributing to cAMP compartmentalization in pulmonary microvascular endothelial cells".
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多种分子和细胞成分的相互作用对于 cAMP 的区室化是必要的。
DOI：
10.1152/ajpcell.00012.2012
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Murray,Fiona
中科院分区：
文献类型：
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作者：
Murray,Fiona
第二信使环磷酸腺苷（cAMP）调节多种细胞反应，包括基因转录、代谢和细胞死亡，以及组织特异性功能，如肺内皮屏障的完整性。cAMP信号传导通过激素和神经递质经由刺激性G亚基与G蛋白偶联受体（GPCR）结合而触发，导致腺苷酸环化酶（AC）的刺激和下游效应物如蛋白激酶A（PKA）、由cAMP直接激活的交换蛋白（EPAC）和环核苷酸门控（CNG）通道的随后激活：环核苷酸磷酸二酯酶（PDE）水解cAMP并终止其作用。目前公认cAMP信号传导不仅是线性级联，而且更复杂，因为参与其产生和作用的每个酶组分表达为不同的同种型，并且cAMP信号传导在离散的亚细胞结构域中组织（2，10）。通过使cAMP接近特定靶点，cAMP的区室化在形成各种激动剂的不同生理反应中是重要的，并且已经成为许多其他信号传导途径的标准模型。例如CNG通道传感器和PKA或EPAC的基于荧光共振能量转移（FRET）的传感器（4）;然而，形成cAMP细胞内梯度的确切机制尚未完全了解。特别是，cAMP途径和扩散屏障的组分的亚细胞锚定，主要由PDE提供，在cAMP信号传导的亚细胞定位和作用中起关键作用。A激酶锚定蛋白（AKAP）螯合cAMP效应物，如PKA、EPAC和PDE，从而在紧邻cAMP靶标的位置形成细胞内特异性信号复合物（2）：亚细胞结构域中特异性AKAP的破坏可以从特定靶标中去除PKA，从而改变cAMP的细胞效应（7）。同时，PDE提供酶屏障以局部降解cAMP并产生具有不同cAMP浓度的多个亚细胞“池”，从而控制cAMP信号的水平和持续性以及下游效应的激活（10）。例如，显性阴性和敲低策略已经显示，个体PDE 4同种型控制限定的亚细胞区室中的cAMP水平，并与特异性GPCR信号级联偶联，从而对于产生细胞内cAMP水平是重要的。
THE SECOND MESSENGER cyclic AMP (cAMP) regulates a wide number of cellular responses, which include gene transcription, metabolism, and cell death, and tissue-specific functions such as the integrity of the endothelial barrier in the lung. cAMP signaling is triggered by binding of hormones and neurotransmitters to G protein-coupled receptors (GPCRs) via the stimulatory G subunit, leading to the stimulation of adenylyl cyclase (AC) and the subsequent activation of downstream effectors such as protein kinase A (PKA), exchange protein directly activated by cAMP (EPAC), and cyclic nucleotidegated (CNG) channels: cyclic nucleotide phosphodiesterases (PDEs) hydrolyze cAMP and terminate its actions. It is currently accepted that cAMP signaling is not merely a linear cascade but more complex, since each enzymatic component involved in its generation and action is expressed as different isoforms and cAMP signaling is organized in discrete subcellular domains (2, 10). Compartmentalization of cAMP, by bringing cAMP close to specific targets, is important in shaping the differential physiological responses of various agonists and has become the standard model for numerous other signaling pathways.Evidence for the spatial and temporal regulation of cAMP has been directly shown with the development of live-cell biosensors, such as CNG-channel sensors and fluorescence resonance energy transfer (FRET)-based sensors for PKA or EPAC (4); however, the exact mechanisms that shape the intracellular gradients of cAMP are not fully understood. In particular, subcellular anchoring of components of the cAMP pathway and diffusional barriers, primarily provided by PDEs, play a key role in the subcellular localization and effect of cAMP signaling. A-kinase anchoring proteins (AKAP) sequester cAMP effectors, such as PKA, EPAC, and PDEs, thereby forming intracellular-specific signaling complexes in close proximity to cAMP targets (2): disruption of specific AKAPs in subcellular domains can remove PKA from a specific target, thus altering the cellular effects of cAMP (7). In parallel, PDEs provide an enzymatic barrier to locally degrade cAMP and generate multiple subcellular “pools” with different cAMP concentrations, thereby controlling the level and persistence of a cAMP signal and activation of downstream effects (10). For example, dominant-negative and knockdown strategies have shown that individual PDE4 isoforms control cAMP levels in defined subcellular compartments and couple to specific GPCR signaling cascades, and are thereby important for generating