Direct activation of PDE5 by cGMP: long-term effects within NO/cGMP signaling.
Direct activation of PDE5 by cGMP: long-term effects within NO/cGMP signaling.
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DOI：
10.1083/jcb.200211041
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发表时间：
2003-03-03
期刊：
影响因子：
--
通讯作者：
Koesling D
中科院分区：
文献类型：
--
作者：
Mullershausen F;Friebe A;Feil R;Thompson WJ;Hofmann F;Koesling D
在血小板中，一氧化氮（NO）诱导的cGMP反应表明cGMP形成和cGMP降解的高度调节的相互作用。最近，我们发现，在NO诱导的cGMP在人血小板的反应，激活和磷酸二酯酶5型（PDE 5）发生。在这里，我们确定环GMP依赖性蛋白激酶I作为负责NO诱导的磷酸化的PDE 5的激酶。然而，我们证明cGMP可以直接激活PDE 5，而不磷酸化血小板胞质溶胶中，最有可能通过结合到监管GAF域。激活的逆转是缓慢的，60分钟后没有完成。磷酸化增强cGMP诱导的激活，使其发生在较低的cGMP浓度。此外，在完整的血小板，持续NO诱导的激活PDE 5长达60分钟的检测。最后，由低NO浓度诱导的cGMP应答的长期脱敏揭示了NO/cGMP信号传导中PDE 5活化的生理相关性。总之，我们认为NO诱导的PDE 5的活化和磷酸化是形成人血小板中cGMP反应的持久负反馈回路的机制，以适应可用的NO量。
In platelets, the nitric oxide (NO)–induced cGMP response is indicative of a highly regulated interplay of cGMP formation and cGMP degradation. Recently, we showed that within the NO-induced cGMP response in human platelets, activation and phosphorylation of phosphodiesterase type 5 (PDE5) occurred. Here, we identify cyclic GMP-dependent protein kinase I as the kinase responsible for the NO-induced PDE5 phosphorylation. However, we demonstrate that cGMP can directly activate PDE5 without phosphorylation in platelet cytosol, most likely via binding to the regulatory GAF domains. The reversal of activation was slow, and was not completed after 60 min. Phosphorylation enhanced the cGMP-induced activation, allowing it to occur at lower cGMP concentrations. Also, in intact platelets, a sustained NO-induced activation of PDE5 for as long as 60 min was detected. Finally, the long-term desensitization of the cGMP response induced by a low NO concentration reveals the physiological relevance of the PDE5 activation within NO/cGMP signaling. In sum, we suggest NO-induced activation and phosphorylation of PDE5 as the mechanism for a long-lasting negative feedback loop shaping the cGMP response in human platelets in order to adapt to the amount of NO available.
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DOI：
10.1111/j.1432-1033.1990.tb15572.x
发表时间：
1990-06-20
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
HUMBERT, P;NIROOMAND, F;BOHME, E
通讯作者：
BOHME, E
DOI：
10.1111/j.1432-1033.1985.tb09010.x
发表时间：
1985-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
OGREID, D;EKANGER, R;DOSKELAND, SO
通讯作者：
DOSKELAND, SO
影响因子：
4.8
作者：
Rybalkin, SD;Rybalkina, IG;Beavo, JA
通讯作者：
Beavo, JA
影响因子：
20.1
作者：
Wegener, JW;Nawrath, H;Feil, R
通讯作者：
Feil, R
DOI：
10.1007/bfb0033670
发表时间：
1999-01-01
期刊：
Reviews of physiology, biochemistry and pharmacology
影响因子：
--
作者：
Juilfs, D M;Soderling, S;Beavo, J A
通讯作者：
Beavo, J A