Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; email:
Annu Rev Pharmacol Toxicol. 2017 Jan 6;57:455-479. doi: 10.1146/annurev-pharmtox-010716-104756. Epub 2016 Oct 12.
Cyclic nucleotide phosphodiesterases (PDEs) form an 11-member superfamily comprising 100 different isoforms that regulate the second messengers cyclic adenosine or guanosine 3',5'-monophosphate (cAMP or cGMP). These PDE isoforms differ with respect to substrate selectivity and their localized control of cAMP and cGMP within nanodomains that target specific cellular pools and synthesis pathways for the cyclic nucleotides. Seven PDE family members are physiologically relevant to regulating cardiac function, disease remodeling of the heart, or both: PDE1 and PDE2, both dual-substrate (cAMP and cGMP) esterases; PDE3, PDE4, and PDE8, which principally hydrolyze cAMP; and PDE5A and PDE9A, which target cGMP. New insights regarding the different roles of PDEs in health and disease and their local signaling control are broadening the potential therapeutic utility for PDE-selective inhibitors. In this review, we discuss these PDEs, focusing on the different mechanisms by which they control cardiac function in health and disease by regulating intracellular nanodomains.
环核苷酸磷酸二酯酶（PDEs）形成了一个由 11 个成员组成的超家族，包含 100 种不同的同工酶，它们调节第二信使环腺苷酸或鸟苷 3'，5'-单磷酸（cAMP 或 cGMP）。这些 PDE 同工酶在底物选择性和它们在纳米域内对 cAMP 和 cGMP 的局部控制方面存在差异，纳米域针对特定的细胞池和环状核苷酸的合成途径。有七个 PDE 家族成员与调节心脏功能、心脏疾病重塑或两者都有关：PDE1 和 PDE2，都是双底物（cAMP 和 cGMP）酯酶；PDE3、PDE4 和 PDE8，主要水解 cAMP；以及 PDE5A 和 PDE9A，靶向 cGMP。关于 PDE 在健康和疾病中的不同作用及其局部信号控制的新见解正在拓宽 PDE 选择性抑制剂的潜在治疗用途。在这篇综述中，我们讨论了这些 PDE，重点讨论了它们通过调节细胞内纳米域来控制健康和疾病中心脏功能的不同机制。
