Francis Sharron H, Blount Mitsi A, Zoraghi Roya, Corbin Jackie D
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232-0615, USA.
Front Biosci. 2005 Sep 1;10:2097-117. doi: 10.2741/1684.
Cyclic GMP is a critical second messenger signaling molecule in many mammalian cell types. It is synthesized by a family of guanylyl cyclases that is activated in response to stimuli from hormones such as natriuretic peptides, members of the guanylin family, and chemical stimuli including nitric oxide and carbon monoxide. The resulting elevation of cGMP modulates myriad physiological processes. Three major groups of cellular proteins bind cGMP specifically at allosteric sites; interaction of cGMP with these sites modulates the activities and functions of other domains within these protein groups to bring about physiological effects. These proteins include the cyclic nucleotide (cN)-dependent protein kinases, cN-gated cation channels, and cGMP-binding phosphodiesterases (PDE). Cyclic GMP also interacts with the catalytic sites of many cN PDEs and with some members of the multi-drug anion transporter family (MRPs) which can extrude nucleotides from cells. The allosteric cN-binding sites in the kinases and the cN-gated channels are evolutionarily and biochemically related, whereas the allosteric cGMP-binding sites in PDEs (also known as GAF domains), the catalytic sites of PDEs , and the ligand-binding sites in the MRPs are evolutionarily and biochemically distinct from each other and from those in the kinase and channel families. The sites that interact with cGMP within each of these groups of proteins have unique properties that provide for cGMP binding. Within a given cell, cGMP can potentially interact with members of all these groups of proteins if they are present. The relative abundance and affinities of these various cGMP-binding sites in conjunction with their subcellular compartmentation, proximity to cyclases and PDEs, and post-translational modification contribute importantly in determining the impact of these respective proteins to cGMP signaling within a particular cell.
环磷酸鸟苷（cGMP）是许多哺乳动物细胞类型中的关键第二信使信号分子。它由一类鸟苷酸环化酶合成，这些酶在受到诸如利钠肽等激素、鸟苷蛋白家族成员的刺激以及包括一氧化氮和一氧化碳在内的化学刺激时被激活。由此导致的cGMP升高调节了无数的生理过程。三大类细胞蛋白在变构位点特异性结合cGMP；cGMP与这些位点的相互作用调节这些蛋白组内其他结构域的活性和功能，从而产生生理效应。这些蛋白包括环核苷酸（cN）依赖性蛋白激酶、cN门控阳离子通道和cGMP结合磷酸二酯酶（PDE）。cGMP还与许多cN PDE的催化位点以及多药阴离子转运蛋白家族（MRP）的一些成员相互作用，后者可将核苷酸排出细胞。激酶和cN门控通道中的变构cN结合位点在进化和生化上相关，而PDE中的变构cGMP结合位点（也称为GAF结构域）、PDE的催化位点以及MRP中的配体结合位点在进化和生化上彼此不同，也与激酶和通道家族中的位点不同。这些蛋白组中每一组与cGMP相互作用的位点都具有独特的特性，以实现cGMP结合。在给定的细胞内，如果存在，cGMP可能与所有这些蛋白组的成员相互作用。这些各种cGMP结合位点的相对丰度和亲和力，连同它们的亚细胞区室化、与环化酶和PDE的接近程度以及翻译后修饰，在确定这些各自的蛋白对特定细胞内cGMP信号传导的影响方面起着重要作用。
