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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Compartmentation and compartment-specific regulation of PDE5 by protein kinase G allows selective cGMP-mediated regulation of platelet functions
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Compartmentation and compartment-specific regulation of PDE5 by protein kinase G allows selective cGMP-mediated regulation of platelet functions

机译：蛋白激酶G对PDE5的区室和区室特异性调节允许选择性cGMP介导的血小板功能调节

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It is generally accepted that nitric oxide (NO) donors, such as sodium nitroprusside (5NP), or phosphodiesterase 5 (PDE5) inhib-itors, including sildenafil, each impact human platelet function. Although a strong correlation exists between the actions of NO donors in platelets and their impact on cGMP, agents such as sildenafil act without increasing global intra-platelet cGMP levels. This study was undertaken to identify how PDE5 inhibitors might act without increasing cGMP. Our data identify PDE5 as an integral component of a protein kinase G1β (PKG1β-containing signaling complex, reported previously to coordinate cGMP-mediated inhibition of inositol-1, 4, 5-trisphosphate receptor type 1 (IP_3R1)-mediated Ca~(2+)-release. PKG1β and PDE5 did not interact in sub-cellular fractions devoid of IP_3R1 and were not recruited to IP_3R1-enriched membranes in response to cGMP-elevating agents. Activation of platelet PKG promoted phosphorylation and activation of the PDE5 fraction tethered to the IP_3R1-PKG complex, an effect not observed for the nontethered PDE5. Based on these findings, we elaborate a model in which PKG selectively activates PDE5 within a defined microdomain in platelets and propose that this mechanism allows spatial and temporal regulation of cGMP signaling in these cells. Recent reports indicate that sildenafil might prove useful in limiting in-stent thrombosis and the thrombotic events associated with the acute coronary syndromes (ACS), situations poorly regulated with currently available therapeutics. We submit that our findings may define a molecular mechanism by which PDE5 inhibition can differentially impact selected cellular functions of platelets, and perhaps of other cell types.
机译：通常接受的一氧化氮（NO）供体，例如硝普钠（5NP）或磷酸二酯酶5（PDE5）抑制剂，包括昔多芬（sildenafil），均会影响人的血小板功能。尽管NO供体在血小板中的作用与其对cGMP的影响之间存在很强的相关性，但西地那非等药物的作用却不会增加总体血小板内cGMP的水平。进行这项研究以鉴定PDE5抑制剂如何在不增加cGMP的情况下发挥作用。我们的数据将PDE5鉴定为蛋白激酶G1β（含PKG1β的信号复合物）的组成部分，先前报道其可协调cGMP介导的对肌醇-1、4、5-三磷酸受体1型（IP_3R1）介导的Ca〜（2）的抑制作用PKG1β和PDE5在没有IP_3R1的亚细胞部分中不相互作用，也没有响应cGMP升高剂而被募集到富含IP_3R1的膜上。基于这些发现，我们建立了一个模型，在该模型中，PKG在血小板中定义的微域内选择性激活PDE5，并提出该机制允许cGMP信号的时空调节。最近的报道表明西地那非可能在限制支架内血栓形成以及与急性冠状动脉综合征（ACS），情境有关的血栓形成事件方面很有用目前可用的疗法对药物的调节不良。我们认为我们的发现可能定义了一种分子机制，通过该分子机制，PDE5抑制作用可以差异地影响血小板以及其他细胞类型的选定细胞功能。

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