cAMP phosphodiesterase-4A1 (PDE4A1) has provided the paradigm for the intracellular targeting of phosphodiesterases, a process that underpins compartmentalized cAMP signalling
cAMP phosphodiesterase-4A1 (PDE4A1) has provided the paradigm for the intracellular targeting of phosphodiesterases, a process that underpins compartmentalized cAMP signalling
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DOI：
10.1042/bst0340504
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发表时间：
2006-08-01
影响因子：
3.9
通讯作者：
Houslay, M. D.
中科院分区：
文献类型：
--
作者：
Huston, E.;Houslay, T. M.;Houslay, M. D.
cAMP信号传导途径的特异性已经表明，单个组分的细胞内靶向赋予信号传导范式一个三维背景，其中它们可以精细地控制信号结果的特异性。与此范例相关的是cAMP被螯合的PDE（磷酸二酯酶）降解。cAMP在细胞内快速扩散，并且在没有空间限制的POE群体的作用的情况下，cAMP梯度不能在细胞内形成和成形以调节靶向效应蛋白。在调节区室化cAMP信号传导中特别重要的是PDE 4家族的isciforms，其由独特的N-末端区域单独定义。我们已经开发并开创了这样的概念，即该N-末端区域的主要功能是赋予特定PDE 4 isciforms在特定信号传导复合物和细胞内位置上的细胞内靶向。这一概念的范式是从我们对PDE 4A 1（RD 1）亚型的原始研究中发展而来的。PDE 4A 1特有的N-末端区域由两个明确定义的螺旋区域组成，螺旋区域由移动的铰链区隔开。阻碍物-2提供核心膜插入模块，螺旋-1促进活细胞中靶向的膜缔合和保真度。PDE 4A 1的N-末端区域不可逆的、Ca 2+依赖性的插入到膜中提供了细胞活化的“长期”记忆。
Specificity of cAMP signalling pathways has shown that the intracellular targeting of the individual components confers a three-dimensional context to the signalling paradigms in which they can exquisitely control the specificity of the outcome of the signal. Pivotal to this paradigm is degradation of cAMP by sequestered PDEs (phosphodiesterases). cAMP rapidly diffuses within cells and, without the action of spatially confined POE populations, cAMP gradients could not be formed and shaped within cells so as to regulate targeted effector proteins. Of particular importance in regulating compartmentalized cAMP signalling are isciforms of the PDE4 family, which are individually defined by unique N-terminal regions. We have developed and pioneered the concept that a major function of this N-terminal region is to confer intracellular targeting of particular PDE4 isciforms on specific signalling complexes and intracellular locations. The paradigm for this concept developed from our original studies on the PDE4A1 (RD1) isoform. The N-terminal region unique to PDE4A1 consists of two well-defined helical regions separated by a mobile hinge region. Helix-2 provides the core membrane-insertion module, with helix-1 facilitating membrane association and fidelity of targeting in living cells. The irreversible, Ca2+-dependent insertion of the N-terminal region of PDE4A1 into membranes provides 'long-term' memory of cell activation.