Polyamine Fluxes via Hemichannels in Glia: Neuronal Network Regulation

多胺通过神经胶质细胞半通道流动：神经元网络调节

• 批准号: 7059809
• 负责人: SERGUEI N SKATCHKOV
• 金额: $ 11.23万
• 依托单位: UNIVERSIDAD CENTRAL DEL CARIBE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7059809
• 关键词: Xenopus; astrocytes; biological signal transduction; cell cell interaction; electrophysiology; excitatory aminoacid; gap junctions; glia; interneurons; laboratory rat; membrane channels; minority institution research support; neural transmission; neuroanatomy; neuroregulation; polyamines; pyramidal cells; spermidine; spermine; tissue /cell preparation

The polyamines, spermine/spermidine (SP/SD), are released in whole brain from unknown sources during neuronal activity. SP/SD dramatically alter the neuronal network and are neuroprotective against NMDA-induced neurotoxicity and ischemia. Intriguingly, endogenous SP and SD are predominantly stored in astrocytes, not in neurons. Our preliminary data suggest that SP/SD uptake and release by astrocytes may occur through unapposed gap junctions (hemichannels). This finding leads us to the novel working hypothesis that SP/SD are synthesized in neurons and permeate (i) connexin hemichannels in glia to ultimately be stored within the glial syncitium. (ii) Neuronal excitation results in a transient fall of [Ca2+]0 and [H+]0 together with increased [K+]0 that facilitates: (iii) opening of hemichannels in glia and (iv) release of SP from glia to the neuronal environment where it can act on AMPA, kainate and NMDA receptors, (v) Increased extracellular SP relieves residual hemichannel block by divalent cations, thus SP works as a positive feedback signal on glial hemichannels. We propose that SP/SD are signaling molecules that underlie a novel regulatory mechanism of neurons by glia. Furthermore, our preliminary experiments suggest that SP itself may facilitate hemichannel unblock, therefore, neuronal excitation may trigger a cascade, resulting in fast hemichannel opening. Here we ask: (i) what is the mechanism of SP permeation through hemichannels in glia, (ii) how is release of SP regulated under physiological conditions and (iii) what are the functional consequences of SP flux through the astrocytic membrane in a cortical slice preparation? These questions will be addressed by examining the mechanism of SP transport through hemichannels, by examining the effect of SP on heterologously expressed Cx hemichannels and by simultaneous recording from interneurons, astrocytes and principal cells while determining the relationship between opening of hemichannels, SP release and alterations in neuronal excitability. These studies will provide a novel mechanism for understanding the newly elucidated role of glial cells in the regulation of neuronal activity and to minimizing neuronal damage during K+-spreading depression, stroke and ischemia.

多胺，精胺/亚精胺(SP/SD)，是在神经元发育过程中从未知来源在整个大脑中释放的 活动。SP/SD显著改变神经元网络，对NMDA诱导的神经毒性具有神经保护作用 缺血症。有趣的是，内源性SP和SD主要储存在星形胶质细胞中，而不是神经元中。我们的预赛 数据表明，星形胶质细胞摄取和释放SP/SD可能通过非对位的缝隙连接(半通道)发生。 这一发现使我们提出了一个新的工作假说，即SP/SD在神经元中合成并渗透到(I)连接蛋白 胶质细胞中的半突细胞最终储存在神经胶质合体内。(Ii)神经元兴奋导致一过性跌倒 [Ca~(2+)]_0和[H~+]_0与增加的[K~+]_0一起促进：(Iii)胶质细胞半突的开放和(Iv) SP从胶质细胞到神经元环境，在那里它可以作用于AMPA、海人藻酸和NMDA受体，(V)增加 胞外SP通过二价阳离子解除残留的半通道阻滞，从而发挥正反馈信号的作用。 神经胶质半突细胞。我们认为，SP/SD是一种信号分子，是一种新的调控机制的基础 神经胶质细胞的神经元。此外，我们的初步实验表明，SP本身可能促进半通道的开放， 因此，神经元兴奋可能触发级联反应，导致快速半通道开放。在这里我们问：(I)什么是 P物质通过神经胶质细胞半突的渗透机制，(II)生理条件下P物质的释放是如何调节的 条件和(Iii)在大脑皮层切片中SP流过星形细胞膜的功能后果是什么 准备？这些问题将通过研究SP通过半通道的传输机制来解决，通过 SP对异源表达的Cx半通道的影响及同步记录 中间神经元、星形胶质细胞和主细胞在确定半脑沟开放与SP的关系时 神经元兴奋性的释放和改变。这些研究将为理解新的 神经胶质细胞在调节神经元活性和减少K+扩散过程中神经元损伤中的作用 抑郁、中风和脑缺血。