Polyamines and Brain Signaling

描述(由申请人提供)： 据报道，多胺(PA)、精胺(SPM)和亚精胺(SPD)具有神经保护作用和延长寿命的作用。在神经元活动和创伤期间，它们从未知来源的整个大脑中释放出来。我们的初步数据表明，内源性SPM和SPD主要储存在脑和视网膜的神经胶质细胞中，而不是神经元中，但合成SPM和SPD的酶在胶质细胞中缺乏。我们还发现了胶质细胞释放PA的许多条件。这些发现使我们得出一个工作假说，即SPM/SPD是从胶质合胞体释放并缓冲在胶质合胞体内的新型胶质调节剂。神经元兴奋导致[Na]o、[Ca~(2+)]o和[H]o下降，[K]o升高，这为神经胶质细胞半小管开放和SPM从胶质细胞释放到神经元环境提供了条件。细胞外SPM的增加可以调节神经元的受体和通道。在这项建议中，我们特别询问：(I)SPM在胶质细胞中渗透和积累的机制是什么，(Ii)SPM的释放是如何调节的，以及(Iii)SPM通过神经胶质膜双向流动的功能后果是什么？这些问题将通过检测SPM的转运机制和SPM在神经胶质-神经元网络中的作用来解决。使用一种新型的SPM生物传感器，我们将监测创伤和正常条件下细胞外SPM浓度的变化。这些研究将阐明SPM作为神经胶质细胞和神经元之间的细胞外信号分子在生理和病理情况下的作用。这一结果将为未来了解和减少中风和脑缺血期间神经元损伤的努力提供重要信息。 公共卫生相关性： 在这个项目中，我们将确定多胺、精胺(SPM)和亚精胺(SPD)在神经胶质细胞中积累和释放的机制以及它们在神经网络中的作用。这些研究将阐明SPM/SPD在生理和病理条件下作为细胞外信号分子在神经胶质细胞和神经元之间的作用。这一结果将为未来了解和减少K传播性抑郁、中风、脑缺血和癫痫期间神经元损伤的努力提供重要信息。

DESCRIPTION (provided by applicant): The polyamines (PA), spermine (SPM) and spermidine (SPD), are reported to be neuroprotective and increase longevity. They are released in whole brain from unknown sources during neuronal activity and trauma. Our preliminary data indicate that endogenous SPM and SPD are predominantly stored in glial cells in brain and retina, not in neurons, but the enzymes that synthesize SPM and SPD are lacking in glial cells. We also find many conditions under which glia release PA. These findings lead us to the working hypothesis that SPM/SPD are novel glio-modulators released from and buffered within the glial syncytium. Neuronal excitation results in a fall of [Na+]o, [Ca2+]o and [H+]o together with increased [K+]o, providing conditions that facilitate opening of hemichannels in glia and release of SPM from glia to the neuronal environment. Increased extracellular SPM can then modulate neuronal receptors and channels. In this proposal we specifically ask: (i) what is the mechanism of SPM permeation and accumulation in glia, (ii) how is release of SPM regulated and (iii) what are the functional consequences of SPM bidirectional flux through the glial membrane? These questions will be addressed by examining mechanisms of SPM transport and the effects of SPM in the glial-neuronal network. Using a novel SPM-biosensor we will monitor extracellular SPM concentration changes during trauma and normal conditions. These studies will elucidate the roles of SPM as an extracellular signaling molecule between glia and neurons in physiological and pathological situations. The results will provide important information for future efforts to understand and minimize neuronal damage during stroke and ischemia. PUBLIC HEALTH RELEVANCE: Project Narrative In this project we will determine the mechanisms of the polyamines spermine (SPM) and spermidine (SPD) accumulation in and release from glia and their role in the neuronal network. These studies will elucidate the roles of SPM/SPD as extracellular signaling molecules between glia and neurons in physiological and pathological conditions. The results will provide important information for future efforts to understand and minimize neuronal damage during K+-spreading depression, stroke, ischemia and epilepsy in the brain.