Mechanism of L channel-mediated neuronal survival

描述（由申请人提供）：细胞机制调节 生存是复杂，包括平行的和潜在的相互作用的 途径。在神经元中，已知一种在血清剥夺中有效的途径， 从增加L钙通道活性开始。本申请集中于 建立细胞内信号传导过程， 有神经保护作用因为我们最近的研究表明， 生长因子-I（IGF-I）部分地通过快速调节 通过IGF-I受体-PT 3-激酶-Akt和src信号转导的L通道 级联，我们还将确定是否IGF-1的生理水平支配 通过增强L通道介导的流入的特定存活途径。 尽管其机制在很大程度上仍不清楚，但L通道诱导的 神经保护正在进行中。几个研究小组已经表明， 通过钙调素促进生存，生存与钙调素水平的升高有关。 核钙水平。因为核钙和钙调素依赖 激酶（CaMK）促进转录，钙依赖性转录 已经提出抗凋亡基因介导IGF-I-神经保护， 缺血我们的数据表明，CaMKIV是保护血清撤出通过L 通道活性，IGF-1在低血糖症中具有保护作用， 通过L通道依赖机制。相反，初步数据表明， 转录因子C/EBPb可能是促凋亡的，拮抗L 通道依赖生存。在这里，我们将建立L 通道介导的内流保护神经元免受毒性损伤，确定：（1） 如果L通道活性、IGF- 1或IGF-1/L通道调节 在缺氧、高血糖或低血糖中具有神经保护作用，（2）如果ser/thr 神经元L通道的初级亚基a1 C的磷酸化 由IGF-1调节，是IGF-1增强所必需的，以及（3）如果L 通道介导的内流，通过直接刺激或通过L 通道增强，激活特定的核信号级联，导致 生存总之，拟议的实验将大大推进我们的研究。 了解调节中枢神经元存活的机制， 神经系统，与糖尿病神经病变特别相关， 创伤性疾病如中风。

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.