Controlling myocyte cGMP: phosphodiesterase 1 joins the fray.
Controlling myocyte cGMP: phosphodiesterase 1 joins the fray.
复制标题
控制肌细胞 cGMP：磷酸二酯酶 1 加入战斗。
DOI：
10.1161/circresaha.109.209700
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发表时间：
2009
影响因子：
20.1
通讯作者：
Takimoto,Eiki
中科院分区：
文献类型：
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作者：
Takimoto,Eiki
CGMP是调节细胞多种功能的细胞内第二信使。在心肌细胞中，cGMP介导一氧化氮和心房利钠肽的作用，而其对应物cAMP介导儿茶酚胺信号传导。每个环核苷酸具有相应的主要靶向蛋白激酶，cAMP的蛋白激酶（PK）A和cGMP的PKG。PKA刺激与增强的收缩性相关，并且可以刺激生长，而PKG充当心脏中的制动器，能够对抗cAMP-PKA收缩刺激并抑制肥大。1重要的是，这些信号级联的持续时间和幅度不仅由环核苷酸的产生决定，而且还由磷酸二酯酶（PDE）催化的水解决定。PDE调节是相当有效的，通常在几秒到几分钟内抑制给定环核苷酸的急剧上升回到基线。2它在细胞内也是区室化的，因此特定的靶蛋白可以由相同的“通用”环核苷酸调节。3多年来，心脏生物学家瞄准的唯一PDE是PDE 3，这是一种主要以cAMP为靶点的PDE，其抑制作用是米力农等药物治疗心力衰竭的基础。然而，该列表最近随着PDE 4作为β-肾上腺素能信号传导和兴奋-收缩偶联的调节剂4和PDE 5调节心脏应激反应的认识而扩展。[1]根据米勒等人在本期《循环研究》中的研究，我们现在可以通过调节肌细胞中的cGMP将PDE 1添加到肥大调节剂的列表中。哺乳动物PDE包含21个基因的酶超家族，根据序列同源性、酶特性和对抑制剂的敏感性，将其分为11种同工酶（PDE 1至PDE 11）。2这些同工酶对cAMP、cGMP或两者具有不同的特异性，并且在多种组织中也有差异表达。PDE 1、PDE 2、PDE 3、PDE 4、PDE 5和PDE 9在心脏中表达，其中PDE 5和PDE 9对cGMP具有高度特异性（表）。2最近的研究已经证明了PDE 5在心脏中对cGMP的调节作用，1尽管目前还不清楚PDE 9的作用。PDE 5在失败的人中上调6
CGMP is a central intracellular second-messenger regu-lating numerous cellular functions. In the cardiac myocyte, cGMP mediates effects of nitric oxide and atrial natriuretic peptide, whereas its counterpart, cAMP, mediates catecholamine signaling. Each cyclic nucleotide has a corresponding primary targeted protein kinase, protein kinase (PK) A for cAMP, and PKG for cGMP. PKA stimulation is associated with enhanced contractility and can stimulate growth, whereas PKG acts as a brake in the heart, capable of countering cAMP–PKA contractile stimulation and inhibiting hypertrophy. 1 Importantly, the duration and magnitude of these signaling cascades are determined not only by generation of cyclic nucleotides, but also by their hydrolysis catalyzed by phosphodiesterases (PDEs). PDE regulation is quite potent, often suppressing an acute rise in a given cyclic nucleotide back to baseline within seconds to minutes. 2 It is also compartmentalized within the cell, so that specific targeted proteins can be regulated by the same “generic” cyclic nucleotide. 3 For many years, the only PDE in the crosshairs for cardiac biologists was PDE3, a principally cAMP-targeted PDE whose inhibition served as the basis for drugs such as milrinone as a heart failure therapy. However, this list was recently expanded with the recognition of PDE4 as a regulator of ß-adrenergic signaling and excitation–contraction coupling, 4 and PDE5 for its regulation of cardiac stress responses. 1 With the study of Miller et al, 5 in this issue of Circulation Research, we can now add PDE1 to the list of hypertrophy regulators, via its modulation of cGMP in the myocyte.The mammalian PDEs comprise a 21 gene superfamily of enzymes grouped into 11 iso-enzymes (PDE1 to PDE11) based on sequence homology, enzymatic properties, and sensitivity to inhibitors. 2 These isoenzymes harbor different specificities to cAMP, cGMP or both, and are also differentially expressed in a variety of tissues. PDE1, PDE2, PDE3, PDE4, PDE5, and PDE9 are expressed in the heart and among these, PDE5 and PDE9 are highly specific to cGMP (Table). 2 Recent studies have demonstrated a role for cGMP modulation by PDE5 in the heart, 1 although the role for PDE9 is unknown at present. PDE5 is upregulated in failing human6