Section on Endocrinology Genetics (M.F.A., F.R.F., E.B., A.H., I.L., R.B.d.A., C.A.S.), Program on Developmental Endocrinology Genetics, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland 20892; Section of Endocrinology (M.F.A.), University Hospital of Brasilia, Faculty of Medicine, University of Brasilia, Brasilia 70840-901, Brazil; Group for Advanced Molecular Investigation (F.R.F., R.B.d.A.), Graduate Program in Health Science, Medical School, Pontificia Universidade Catolica do Paraná, Curitiba 80215-901, Brazil; Cardiovascular Pulmonary Branch (F.A., V.M.), National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland 20892; and Pediatric Endocrinology Inter-Institute Training Program (C.A.S.), NICHD, NIH, Bethesda, Maryland 20892.
Endocr Rev. 2014 Apr;35(2):195-233. doi: 10.1210/er.2013-1053. Epub 2013 Dec 5.
Cyclic nucleotide phosphodiesterases (PDEs) are enzymes that have the unique function of terminating cyclic nucleotide signaling by catalyzing the hydrolysis of cAMP and GMP. They are critical regulators of the intracellular concentrations of cAMP and cGMP as well as of their signaling pathways and downstream biological effects. PDEs have been exploited pharmacologically for more than half a century, and some of the most successful drugs worldwide today affect PDE function. Recently, mutations in PDE genes have been identified as causative of certain human genetic diseases; even more recently, functional variants of PDE genes have been suggested to play a potential role in predisposition to tumors and/or cancer, especially in cAMP-sensitive tissues. Mouse models have been developed that point to wide developmental effects of PDEs from heart function to reproduction, to tumors, and beyond. This review brings together knowledge from a variety of disciplines (biochemistry and pharmacology, oncology, endocrinology, and reproductive sciences) with emphasis on recent research on PDEs, how PDEs affect cAMP and cGMP signaling in health and disease, and what pharmacological exploitations of PDEs may be useful in modulating cyclic nucleotide signaling in a way that prevents or treats certain human diseases.
环核苷酸磷酸二酯酶（PDEs）是一类具有独特功能的酶，能够通过催化 cAMP 和 GMP 的水解来终止环核苷酸信号。它们是细胞内 cAMP 和 cGMP 浓度及其信号通路和下游生物学效应的关键调节因子。PDE 已经被药理学利用了半个多世纪，目前全球最成功的一些药物都作用于 PDE 的功能。最近，已经鉴定出 PDE 基因的突变是某些人类遗传疾病的原因；最近，PDE 基因的功能变体被认为在肿瘤和/或癌症易感性中发挥潜在作用，特别是在 cAMP 敏感组织中。已经开发出了小鼠模型，这些模型指出 PDE 在从心脏功能到生殖、肿瘤等方面具有广泛的发育作用。本综述汇集了来自多个学科（生物化学和药理学、肿瘤学、内分泌学和生殖科学）的知识，重点介绍了最近关于 PDE 的研究，PDE 如何在健康和疾病中影响 cAMP 和 cGMP 信号，以及 PDE 的药理学利用如何以预防或治疗某些人类疾病的方式调节环核苷酸信号。
