Differential Association of Phosphodiesterase 4D Isoforms with β2-Adrenoceptor in Cardiac Myocytes
Differential Association of Phosphodiesterase 4D Isoforms with β2-Adrenoceptor in Cardiac Myocytes
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DOI：
10.1074/jbc.m109.020388
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发表时间：
2009-12-04
影响因子：
4.8
通讯作者：
Xiang, Yang
中科院分区：
文献类型：
--
作者：
De Arcangelis, Vania;Liu, Ruijie;Xiang, Yang
CAMP和蛋白激酶A(PKA)的激活是应激状态下β-肾上腺素能刺激的关键信号机制。β(1)和β(2)肾上腺素受体(ARs)亚型均可诱导cAMP积聚，但在心肌收缩和心肌细胞凋亡中起着不同的作用。通过受体和cAMP特异性磷酸二酯酶之间的复合体组装来控制cAMP/PKA活性的不同，导致了不同的生物学结果。在这里，我们证明了β(2)受体与一组在心肌细胞中表达的PDE4D亚型形成信号复合体。PDE4D9和PDE4D8在静息状态下与β(2)AR结合；然而，激动剂刺激导致PDE4D9从受体解离，但PDE4D8重新聚集到受体。激动剂刺激还可诱导PDE4D5重新聚集到β(2)AR。此外，受体相关的PDE4D亚型在控制cAMP活性、调节受体的PKA磷酸化和心肌细胞收缩速率反应中发挥着明显的作用。用短发夹状RNA敲除PDE4D9可增强β(2)AR诱导的cAMP信号，而敲除PDE4D8仅略微延长受体诱导的cAMP信号。抑制PDE4D9和PDE4D5增强收缩速率的基线水平，而抑制PDE4D9和PDE4D8增强激活β(2)AR时的最大收缩速率增加。我们的数据强调了β(2)AR相关的磷酸二酯酶对细胞内cAMP的复杂调节，以增强受体信号对生理反应的特异性。
cAMP and protein kinase A (PKA) activation represents a key signaling mechanism upon beta-adrenergic stimulation under stress. Both beta(1)- and beta(2)-adrenoreceptor (ARs) subtypes induce cAMP accumulation, yet play distinct roles in cardiac contraction and myocyte apoptosis. Differences in controlling cAMP/PKA activities through the assembly of complexes between the receptors and cAMP-specific phosphodiesterases contribute to the distinct biological outcomes. Here, we demonstrate that beta(2)ARs form signaling complexes with a set of PDE4D isoforms expressed in cardiac myocytes. PDE4D9 and PDE4D8 bind to the beta(2)AR at resting conditions; however, agonist stimulation induces dissociation of PDE4D9 from the receptor but recruitment of PDE4D8 to the receptor. Agonist stimulation also induces recruitment of PDE4D5 to the beta(2)AR. Moreover, the receptor-associated PDE4D isoforms play distinct roles in controlling cAMP activities and regulating the PKA phosphorylation of the receptor and myocyte contraction rate responses. Knockdown of PDE4D9 with short hairpin RNA enhances the beta(2)AR-induced cAMP signaling, whereas knockdown of PDE4D8 only slightly prolongs the receptor-induced cAMP signaling in myocytes. Inhibition of PDE4D9 and PDE4D5 enhances the base-line levels of contraction rates, whereas inhibition of PDE4D9 and PDE4D8 enhances the maximal contraction rate increases upon activation of beta(2)AR. Our data underscore the complex regulation of intracellular cAMP by beta(2)AR-associated phosphodiesterase enzymes to enforce the specificity of the receptor signaling for physiological responses.