Local InsP3-dependent perinuclear Ca2+ signaling in cardiac myocyte excitation-transcription coupling
Local InsP3-dependent perinuclear Ca2+ signaling in cardiac myocyte excitation-transcription coupling
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DOI：
10.1172/jci27374
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发表时间：
2006-03-01
影响因子：
15.9
通讯作者：
Bers, DM
中科院分区：
文献类型：
--
作者：
Wu, X;Zhang, T;Bers, DM
以往的研究表明，钙调蛋白(CaM)和钙调素依赖的蛋白激酶II(CaMKII)在某种程度上参与了心肌肥大信号的传递，心肌细胞中的肌醇1，4，5-三磷酸受体(InSP(3)Rs)主要位于核膜中，在那里它们与CaMKII有关，而II类组蛋白脱乙酰酶(如HDAC5)则抑制肥大基因的转录。此外，内皮素-1(ET-1)等神经体液刺激导致心肌肥大时，HDAC的磷酸化可激活HDAC核输出，从而调节心肌细胞转录。在这里，我们展示了这三个问题在成人心室肌细胞中的详细机制汇聚。我们发现，ET-1激活质膜G蛋白偶联受体和InSP(3)的产生，通过Insp(3)R诱导局部核膜钙释放，这种局部钙释放激活核CaMKII，从而触发HDAC5磷酸化和核输出(去抑制转录)。值得注意的是，这种钙依赖的途径不能被导致每次心跳收缩的全球钙瞬变所激活。这种新的局部钙离子信号在激发-转录偶联中与参与兴奋-收缩偶联的信号相似，但与之分离(和绝缘)。因此，心肌细胞可以区分同时参与收缩激活的局部和全局钙信号与那些针对基因表达的信号。
Previous work showed that calmodulin (CaM) and Ca2+-CaM-dependent protein kinase II (CaMKII) are somehow involved in cardiac hypertrophic signaling, that inositol 1,4,5-trisphosphate receptors (InsP(3)Rs) in ventricular myocytes are mainly in the nuclear envelope, where they associate with CaMKII, and that class II histone deacetylases (e.g., HDAC5) suppress hypertrophic gene transcription. Furthermore, HDAC phosphorylation in response to neurohumoral stimuli that induce hypertrophy, such as endothelin-1 (ET-1), activates HDAC nuclear export, thereby regulating cardiac myocyte transcription. Here we demonstrate a detailed mechanistic convergence of these 3 issues in adult ventricular myocytes. We show that ET-1, which activates plasmalemmal G protein-coupled receptors and InsP(3) production, elicits local nuclear envelope Ca2+ release via InsP(3)R. This local Ca2+ release activates nuclear CaMKII, which triggers HDAC5 phosphorylation and nuclear export (derepressing transcription). Remarkably, this Ca2+-dependent pathway cannot be activated by the global Ca2+ transients that cause contraction at each heartbeat. This novel local Ca2+ signaling in excitation-transcription coupling is analogous to but separate (and insulated) from that involved in excitation-contraction coupling. Thus, myocytes can distinguish simultaneous local and global Ca2+ signals involved in contractile activation from those targeting gene expression.