Phosphodiesterase 4 and phosphatase 2A differentially regulate cAMP/protein kinase a signaling for cardiac myocyte contraction under stimulation of beta1 adrenergic receptor.
Phosphodiesterase 4 and phosphatase 2A differentially regulate cAMP/protein kinase a signaling for cardiac myocyte contraction under stimulation of beta1 adrenergic receptor.
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磷酸二酯酶4和磷酸酶2a差异调节CAMP/蛋白激酶A信号在刺激β1肾上腺素能受体下进行心肌细胞收缩。
DOI：
10.1124/mol.108.049718
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发表时间：
2008-11
影响因子：
3.6
通讯作者：
Xiang Y
中科院分区：
文献类型：
--
作者：
De Arcangelis V;Soto D;Xiang Y
β肾上腺素能受体（βAR）的激活可诱导严格控制的cAMP/蛋白激酶A（PKA）活性，以确保动物心脏的激动剂剂量依赖性和可饱和的收缩反应。我们发现，在1 μM的剂量下，异丙肾上腺素刺激β1AR诱导心肌细胞产生最大收缩反应;然而，随着激动剂浓度的增加，cAMP积累继续增加。剂量依赖性cAMP蓄积由水解cAMP的负调节剂磷酸二酯酶4（PDE 4）严格控制。在1 nM异丙肾上腺素下，cAMP蓄积最小，因为PDE 4水解cAMP，导致受磷蛋白和肌钙蛋白I（TnI）的PKA磷酸化和收缩反应小幅增加。rolipram抑制PDE 4活性增强cAMP积累，产生受磷蛋白和TnI的最大PKA磷酸化，以及肌细胞收缩反应。相比之下，在10 μM异丙肾上腺素下，尽管PDE 4有负面作用，但cAMP积累足以使受磷蛋白和TnI的PKA磷酸化达到最大。用咯利普兰抑制PDE 4增强cAMP积累，但不增强PKA磷酸化和收缩反应。10 μM异丙肾上腺素激活β1AR后，PKA和蛋白磷酸酶2A（PP 2A）的活性均增强，PP 2A被募集到PKA/A激酶锚定蛋白复合物中。用冈田酸抑制PP 2A进一步增强受磷蛋白和TnI的磷酸化以及10 μM异丙肾上腺素诱导的收缩反应。因此，PP 2A在限制受磷蛋白和TnI的PKA磷酸化以促进β1AR刺激下的心肌细胞收缩反应中起关键作用。
Activation of the β adrenergic receptor (βAR) induces a tightly controlled cAMP/protein kinase A (PKA) activity to ensure an agonist dose-dependent and saturable contraction response in animal heart. We have found that stimulation of β1AR by isoproterenol induces maximal contraction responses at the dose of 1 μM in cardiac myocytes; however, cAMP accumulation continues to increase with higher agonist concentrations. Dose-dependent cAMP accumulation is tightly controlled by negative regulator phosphodiesterase 4 (PDE4) that hydrolyzes cAMP. At 1 nM isoproterenol, cAMP accumulation is minimal because of the hydrolysis of cAMP by PDE4, which leads to a small increase in PKA phosphorylation of phospholamban and troponin I (TnI), and contraction responses. Inhibition of PDE4 activity with rolipram enhances cAMP accumulation, yields maximal PKA phosphorylation of phospholamban and TnI, and myocyte contraction responses. In contrast, at 10 μM isoproterenol, despite the negative effect of PDE4, cAMP accumulation is sufficient for maximal PKA phosphorylation of phospholamban and TnI. Inhibition of PDE4 with rolipram enhances cAMP accumulation, but not PKA phosphorylation and contraction responses. It is interesting that activities of both PKA and protein phosphatase 2A (PP2A) are enhanced under β1AR activation with 10 μM isoproterenol, and PP2A is recruited to PKA/A kinase-anchoring protein complex. Inhibition of PP2A with okadaic acid further enhances the phosphorylation of phospholamban and TnI as well as contraction responses induced by 10 μM isoproterenol. Therefore, PP2A plays a key role in limiting PKA phosphorylation of phospholamban and TnI for myocyte contraction responses under β1AR stimulation.
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