Coupling of Ca2+ to CREB activation and gene expression in intact cerebral arteries from mouse -: Roles of ryanodine receptors and voltage-dependent Ca2+ channels
Coupling of Ca2+ to CREB activation and gene expression in intact cerebral arteries from mouse -: Roles of ryanodine receptors and voltage-dependent Ca2+ channels
复制标题
DOI：
10.1161/01.res.86.7.760
复制
发表时间：
2000-04-14
影响因子：
20.1
通讯作者：
Nelson, MT
中科院分区：
文献类型：
--
作者：
Cartin, L;Lounsbury, KM;Nelson, MT
血管系统的病理变化以钙离子处理的变化和基因表达的变化为特征。在神经元和其他类型的细胞中，[Ca~(2+)](I)经常驱动基因表达的变化。然而，钙信号与血管平滑肌基因表达之间的关系还不是很清楚。本研究探讨电压依赖性L型钙通道(VDCC)的钙内流和兰尼定受体(RYR)的钙释放激活转录因子cAMP反应元件结合蛋白(CREB)和增加c-fos水平的能力。膜去极化增加完整小鼠脑动脉中磷酸化CREB(P-CREB)的核染色比例和c-fos基因表达水平。Ryanodine抑制RyRs，增加P-CREB染色和c-fos水平。腺苷环化酶激活剂Forsklin和NO供体硝普钠可增加P-CREB和c-fos水平。VDCCs的抑制剂尼索地平可逆转去极化和兰诺定对P-CREB和c-fos水平的影响，但不能逆转Forsklin或硝普钠的作用。抑制钙/钙调蛋白依赖的蛋白激酶(CaM)可阻断膜去极化引起的P-CREB和c-fos水平的升高，提示CaM在钙离子内流到CREB介导的c-fos水平变化的通路中起重要作用。我们的数据表明，膜去极化通过激活VDCCs增加[Ca~(2+)]，导致P-CREB和c-fos增加，RyRs通过间接调节VDCC进入Ca~(2+)而对这一途径产生深远影响。这些结果首次证明了钙离子对动脉平滑肌中CREB和c-fos的调节作用。
Pathological changes of the vasculature are characterized by changes in Ca2+ handling and alterations in gene expression. In neurons and other cell types, [Ca2+](i) often drives changes in gene expression. However, the relationship between Ca2+ signaling and gene expression in vascular smooth muscle is not well understood. This study examines the ability of Ca2+ influx through voltage-dependent, L-type Ca2+ channels (VDCCs) and Ca2+ release through ryanodine receptors (RyRs) to activate the transcription factor, cAMP-responsive element binding protein (CREB), and increase c-fos levels in intact cerebral arteries. Membrane depolarization increased the fraction of nuclei staining for phosphorylated CREB (P-CREB) and levels of c-fos mRNA in intact mouse cerebral arteries. Ryanodine, which inhibits RyRs, increased P-CREB staining and c-fos levels. Forskolin, an activator of adenylyl cyclase, and sodium nitroprusside, an NO donor, increased P-CREB and c-fos levels. Nisoldipine, an inhibitor of VDCCs, reversed the effects of depolarization and ryanodine on P-CREB and c-fos levels, but not the effects of forskolin or sodium nitroprusside. Inhibition of Ca2+/calmodulin-dependent protein kinase (CaM kinase) blocked increases in P-CREB and c-fos levels seen with membrane depolarization, suggesting that CaM kinase has an important role in the pathway leading from Ca2+ influx to CREB-mediated changes in c-fos levels. Our data suggest that membrane depolarization increases [Ca2+], through activation of VDCCs, leading to increased P-CREB and c-fos, and that RyRs have a profound effect on this pathway by indirectly regulating Ca2+ entry through VDCCs. These results provide the first evidence of Ca2+ regulation of CREB and c-fos in arterial smooth muscle.