Protein kinase a type I and type II define distinct intracellular signaling compartments
Protein kinase a type I and type II define distinct intracellular signaling compartments
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DOI：
10.1161/circresaha.108.174813
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发表时间：
2008-10-10
影响因子：
20.1
通讯作者：
Zaccolo, Manuela
中科院分区：
文献类型：
--
作者：
Di Benedetto, Giulietta;Zoccarato, Anna;Zaccolo, Manuela
蛋白激酶A （PKA）是一种关键的调节酶，被cAMP激活后，可以调节多种细胞功能。I型和II型PKA同工异构体具有不同的结构特征和生化特征，因此具有非冗余功能。然而，在同一细胞中表达的不同PKA亚型如何在相同的可溶性细胞内信使cAMP的激活下执行不同的功能仍有待确定。在这里，我们提供了PKA亚型在心肌细胞中不同功能的机制，并证明PKA- ri和PKA- rii通过与AKAPs （a激酶锚定蛋白）结合，被拴在不同的亚细胞区域，从而定义了不同的细胞内信号传导区。在这些区室中，PKA-RI和PKA-RII对特定G蛋白偶联受体激动剂产生的不同的、空间受限的cAMP信号作出反应，并由cAMP降解磷酸二酯酶的独特亚群调节。因此，个体PKA亚型的选择性激活导致下游靶标的独特亚群的磷酸化。
Protein kinase A (PKA) is a key regulatory enzyme that, on activation by cAMP, modulates a wide variety of cellular functions. PKA isoforms type I and type II possess different structural features and biochemical characteristics, resulting in nonredundant function. However, how different PKA isoforms expressed in the same cell manage to perform distinct functions on activation by the same soluble intracellular messenger, cAMP, remains to be established. Here, we provide a mechanism for the different function of PKA isoforms subsets in cardiac myocytes and demonstrate that PKA-RI and PKA-RII, by binding to AKAPs (A kinase anchoring proteins), are tethered to different subcellular locales, thus defining distinct intracellular signaling compartments. Within such compartments, PKA-RI and PKA-RII respond to distinct, spatially restricted cAMP signals generated in response to specific G protein-coupled receptor agonists and regulated by unique subsets of the cAMP degrading phosphodiesterases. The selective activation of individual PKA isoforms thus leads to phosphorylation of unique subsets of downstream targets.