Cyclic GMP as substrate and regulator of cyclic nucleotide phosphodiesterases (PDEs).
Cyclic GMP as substrate and regulator of cyclic nucleotide phosphodiesterases (PDEs).
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DOI：
10.1007/bfb0033670
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发表时间：
1999-01-01
期刊：
影响因子：
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通讯作者：
Beavo, J A
中科院分区：
文献类型：
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作者：
Juilfs, D M;Soderling, S;Beavo, J A
环核苷酸磷酸二酯酶（PDEs）的调节，这些酶负责第二信使，cAMP和cGMP的降解，在调节各种激素，神经递质和其他激动剂（包括光）的多种作用方面是重要的。细胞对这些效应物反应的强度和持续时间取决于细胞内表达的各种PDE亚型的活性。在过去二十年中，已经作出了广泛的努力来查明和描述这些发展中国家的特点。对pde调控的细胞内信号通路的描述和表征使人们越来越认识到它们在调节生理反应中的重要性。迄今为止，已经鉴定和表征了真核生物pde的8个家族。目前接受的这些pde命名法的更新列表可在万维网上找到，网址如下：http://weber。美国华盛顿。edu/Npde/。6个PDE家族能够被cGMP调节或水解cGMP （Beavo, 1995）。许多pde已被证明是许多途径的重要生理调节剂，包括视力（PDE6）（Farber, 1995），男性勃起反应（PDE5）（Boolell等人，1996），肾上腺类固醇生成（PDE2）（MacFarland等人，1991），心脏收缩（PDE2和PDE3）（RivetBastide等人，1997）和胰岛素/IGF-1作用（Zhao等人，1997）。每个PDE家族都具有独特的初级结构、调节特性、水解特异性和抑制剂特征。此外，与同一物种内的其他科成员相比，每个科成员在物种间表现出更高的序列同源性。大多数PDE家族由来自多个基因的蛋白质组成。此外，许多PDE基因发生多剪接变异，导致蛋白质具有独特的末端。很可能还有更多的个体成员和整个家庭尚未被发现。所有pde在羧基端附近都有大约270个氨基酸的同源区域，这些同源区域被认为包含催化结构域（Charbonneau, 1990）。该区域赋予每个PDE家族独特的底物特异性。cGMP结合PDEs （PDE5）、光感受器PDEs （PDE6）和最近描述的PDE9家族特异性水解cGMP。PDE9家族！它是PDE超家族的最新成员，将在后面的小节中进行更详细的讨论。与cgmp特异性PDEs不同，钙/钙调素刺激的PDEs （PDE1）和cgmp刺激的PDEs （PDE2s）可以水解这两种环核苷酸。虽然cgmp抑制的PDE （PDE3）的催化结构域可以结合两个环核苷酸，
The regulation of cyclic nucleotide phosphodiesterases (PDEs), those enzymes responsible for the degradation of the second messengers, cAMP and cGMP, is important in mediating the diverse effects of various hormones, neurotransmitters and other agonists, including light. The intensity and duration of the cellular response to these effectors is dependent upon the activity of the various PDE isoforms expressed within a cell. During the past two decades extensive efforts have been made towards identifying and characterizing these PDEs. The description and the characterization of the intracellular signaling pathways that PDEs regulate has led to the growing realization of the importance they play in regulating physiologic responses. To date eight families of eukaryotic PDEs have been identified and characterized. An updated list of the currently accepted nomenclature for these PDEs can be found on the World Wide Web at the following URL: http://weber. u. washington. edu/Npde/. Six of the PDE families are capable of either being regulated by cGMP or hydrolyzing cGMP (Beavo, 1995). Many of these PDEs have been demonstrated to be important physiologic regulators of a number of pathways including vision (PDE6)(Farber, 1995), the male erectile response (PDE5)(Boolell et al. 1996), adrenal steroidogenesis (PDE2)(MacFarland et al. 1991), cardiac contractility (PDE2 and PDE3)(RivetBastide et al. 1997), and insulin/IGF-1 action (Zhao et al. 1997). Each of the PDE families is distinguished by a unique primary structure, regulatory properties, hydrolytic specificity and inhibitor profiles. Moreover, each family member exhibits higher sequence homology to its counterpart across species than to members of other families within a species. Most of the PDE families consist of proteins derived from more than one gene. In addition, multiple splice variants occur for many of the PDE genes resulting in proteins with unique termini. It is likely that more individual members and entire families are yet to be discovered. All PDEs have an approximately 270 amino acid region of homology near the carboxy terminus believed to encompass the catalytic domain (Charbonneau, 1990). This region confers a unique substrate specificity for each PDE family. The cGMP-binding PDEs (PDE5), the photoreceptor PDEs (PDE6) and the recently described PDE9 family specifically hydrolyze cGMP. The PDE9 family! s the newest member of the PDE superfamily and will be discussed in more detail in a later section. Unlike the cGMP-specific PDEs, the calcium/calmodulin-stimulated PDEs (PDE1) and the cGMP-stimulated PDEs (PDE2s) can hydrolyze both cyclic nucleotides. Although the catalytic domain of the cGMP-inhibited PDE (PDE3) can bind both cyclic nucleotides,