Kirk Jonathan A, Holewinski Ronald J, Crowgey Erin L, Van Eyk Jennifer E
Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University, Maywood, IL, USA.
Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Proteomics. 2016 Mar;16(5):894-905. doi: 10.1002/pmic.201500401. Epub 2016 Feb 16.
The protective role of cyclic guanosine monophosphate (cGMP)-stimulated protein kinase G (PKG) in the heart makes it an attractive target for therapeutic drug development to treat a variety of cardiac diseases. Phosphodiesterases degrade cGMP, thus phosphodiesterase inhibitors that can increase PKG are of translational interest and the subject of ongoing human trials. PKG signaling is complex, however, and understanding its downstream phosphorylation targets and upstream regulation are necessary steps toward safe and efficacious drug development. Proteomic technologies have paved the way for assays that allow us to peer broadly into signaling minutia, including protein quantity changes and phosphorylation events. However, there are persistent challenges to the proteomic study of PKG, such as the impact of the expression of different PKG isoforms, changes in its localization within the cell, and alterations caused by oxidative stress. PKG signaling is also dependent upon sex and potentially the genetic and epigenetic background of the individual. Thus, the rigorous application of proteomics to the field will be necessary to address how these effectors can alter PKG signaling and interfere with pharmacological interventions. This review will summarize PKG signaling, how it is being targeted clinically, and the proteomic challenges and techniques that are being used to study it.
环磷酸鸟苷（cGMP）刺激的蛋白激酶G（PKG）在心脏中的保护作用使其成为治疗多种心脏病的治疗药物开发的有吸引力的靶点。磷酸二酯酶会降解cGMP，因此能够增加PKG的磷酸二酯酶抑制剂具有转化研究价值，并且正在进行人体试验。然而，PKG信号传导很复杂，了解其下游磷酸化靶点和上游调节是实现安全有效的药物开发的必要步骤。蛋白质组学技术为相关检测方法铺平了道路，使我们能够广泛深入地研究信号细节，包括蛋白质数量变化和磷酸化事件。然而，PKG的蛋白质组学研究仍存在持续的挑战，例如不同PKG亚型表达的影响、其在细胞内定位的变化以及氧化应激引起的改变。PKG信号传导还取决于性别以及个体的遗传和表观遗传背景。因此，必须将蛋白质组学严格应用于该领域，以解决这些效应器如何改变PKG信号传导并干扰药物干预的问题。本综述将总结PKG信号传导、其在临床上的靶向方式以及用于研究它的蛋白质组学挑战和技术。
