Mechanism of L channel-mediated neuronal survival

L通道介导的神经元存活机制

• 批准号: 6540146
• 负责人: JOHN MARSHALL
• 金额: $ 30.97万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-15 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6540146
• 关键词: apoptosis; biological signal transduction; calcium channel; calcium flux; calmodulin dependent protein kinase; diabetic neuropathy; electrophysiology; gel mobility shift assay; hyperglycemia; hypoglycemia; hypoxia; insulinlike growth factor; neurons; neuroprotectants; phosphorylation; protein kinase; stroke

DESCRIPTION (provided by applicant): The cellular mechanisms regulating survival are complex and comprise parallel and potentially interactive pathways. In neurons, one pathway effective in serum-deprivation is known to commence with increased L calcium channel activity. This application focuses on establishing the intracellular signaling processes by which L channel activity is neuroprotective. Because our recent work has demonstrated that insulin-like growth factor-l (IGF-l) is protective through, in part, the rapid regulation of L channels via an IGF-l receptor-PT 3-kinase-Akt and src signal transduction cascade, we will also determine whether physiological levels of IGF-1 govern particular survival pathways via potentiating L channel-mediated influx. Although the mechanisms remain largely unknown, studies on L channel-induced neuroprotection are now underway. Several groups have shown that calcium influx promotes survival via calmodulin and that survival is associated with a rise in nuclear calcium levels. Because nuclear calcium and calmodulin-dependent kinases (CaMK) promote transcription, calcium-dependent transcription of anti-apoptotic genes has been suggested to mediate IGF-l-neuroprotection in ischemia. Our data indicate that CaMKIV is protective in serum withdrawal via L channel activity and that IGF-1 is protective in hypoglycemia, partially through an L channel-dependent mechanism. Conversely, preliminary data suggest that the transcription factor, C/EBPb, may be pro-apoptotic, antagonizing L channel-dependent survival. Here, we will establish the means by which L channel-mediated influx protects neurons from toxic insults, determining: (1) if L channel activity, IGF- 1 or IGF- i/L channel-modulation are neuroprotective in hypoxia, hyper- or hypoglycemia, (2) if ser/thr phosphorylation of neuronal a1C, the primary subunit of the neuronal L channel modulated by IGF-1, is essential for IGF-1-potentiation, and (3) if L channel-mediated influx, either by direct stimulation or via L channel-potentiation, activates specific nuclear signaling cascades, leading to survival. Together, the proposed experiments will significantly advance our understanding of the mechanisms that regulate neuronal survival in the central nervous system, with particular relevance to diabetic neuropathies and traumatic disorders such as stroke.

描述(申请人提供)：细胞机制调节 生存是复杂的，由并行的和潜在的互动组成 小路。在神经元中，已知有一条在血清剥夺中有效的途径是 首先增加L钙通道的活性。此应用程序侧重于 建立L通道活动的细胞内信号转导过程 具有神经保护作用。因为我们最近的研究表明，类胰岛素 生长因子-L(胰岛素样生长因子-L)具有保护作用，部分是通过快速调节 L通过胰岛素样生长因子-L受体-PT3-激酶-Akt和src信号转导通路 我们还将确定IGF-1的生理水平是否决定了 通过增强L经络介导的内流，形成特定的生存通路。 虽然其作用机制尚不清楚，但对L经络作用的研究 神经保护现在正在进行中。几个研究小组已经证明，钙离子内流 通过钙调素促进存活率，存活率与 核内的钙含量。因为核内钙和钙调蛋白依赖 激酶(CaMK)促进转录，钙依赖的转录 抗凋亡基因被认为介导胰岛素样生长因子-L-神经保护作用 缺血症。我们的数据表明，CaMKIV通过L途径对血清提取具有保护作用 通道活性和IGF-1对低血糖有部分保护作用 通过L的渠道依赖机制。相反，初步数据显示 转录因子C/EBpb可能是促凋亡的，拮抗L 依靠渠道生存。在这里，我们将确立L通过何种手段 通道介导的内流保护神经元免受毒性伤害，决定：(1) 如果L信道活动，则IGF1或IGF1/L信道调制 低氧、高血糖或低血糖时的神经保护，(2)如果严重/严重 神经元L通道初级亚单位A1C的磷酸化 在胰岛素样生长因子-1的调节下，对胰岛素样生长因子-1的增强是必不可少的；(3)如果L 直接刺激或通过L的渠道中介流入 通道增强，激活特定的核信号级联，导致 生死存亡。总之，拟议的实验将显著推进我们的 对中枢神经系统神经元存活调控机制的认识 神经系统，尤其与糖尿病神经病变和 创伤性障碍，如中风。