Compartmentalized cyclic nucleotides have opposing effects on regulation of hypertrophic phospholipase Cε signaling in cardiac myocytes.
Compartmentalized cyclic nucleotides have opposing effects on regulation of hypertrophic phospholipase Cε signaling in cardiac myocytes.
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区室化的环核苷酸对心肌细胞中肥大性磷脂酶 Cγ 信号传导的调节具有相反的作用。
DOI：
10.1016/j.yjmcc.2018.06.002
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发表时间：
2018
影响因子：
5
通讯作者：
Smrcka,AlanV
中科院分区：
文献类型：
--
作者：
Nash,CraigA;Brown,LorenM;Malik,Sundeep;Cheng,Xiaodong;Smrcka,AlanV
在心肌细胞中，由cAMP激活的交换因子（Epac）的激活导致高尔基体中磷脂酶Cε（PLCε）依赖性的磷脂酰肌醇4-磷酸（PI 4P）水解的激活，这是心脏肥大发展的关键过程。在此，我们发现，在存在广谱磷酸二酯酶（PDE）抑制剂IBMX的情况下，β-肾上腺素能受体（βAR）刺激并不刺激该通路，但选择性抑制PDE 3则显示β AR依赖的PI 4P耗竭。另一方面，选择性抑制PDE 2或PDE 9A可阻断PLCε对内皮素-1（ET-1）和cAMP依赖的PI 4 P的水解。直接激活蛋白激酶A（PKA）、蛋白激酶G（PKG）或心房利钠因子（ANF）受体可阻断PI 4P水解对多种上游刺激的反应。这些结果揭示了不同的环核苷酸池，其通过PKA/PKG抑制高尔基体处的PLCε，或通过Epac激活高尔基体处的PLCε。这些数据共同揭示了ANF和选择性PDE抑制剂可以防止心脏肥大的新机制。
In cardiac myocytes activation of an exchange factor activated by cAMP (Epac) leads to activation of phospholipase Cε (PLCε)-dependent hydrolysis of phosphatidylinositol 4-phosphate (PI4P) in the Golgi apparatus a process critical for development of cardiac hypertrophy. Here we show that β-adrenergic receptor (βAR) stimulation does not stimulate this pathway in the presence of the broad spectrum phosphodiesterase (PDE) inhibitor IBMX, butselectivePDE3 inhibition revealed βAR-dependent PI4P depletion. On the other hand, selective inhibition of PDE2 or PDE9Ablockedendothelin-1 (ET-1) and cAMP-dependent PI4P hydrolysis by PLCε. Direct activation of protein kinase A (PKA), protein kinase G (PKG), or the atrial natriuretic factor (ANF) receptor abolished PI4P hydrolysis in response to multiple upstream stimuli. These results reveal distinct pools of cyclic nucleotides that either inhibit PLCε at the Golgi through PKA/PKG, or activate PLCε at the Golgi through Epac. These data together reveal a new mechanism by which ANF and selective PDE inhibitors can protect against cardiac hypertrophy.