Polyamine Fluxes via Hemichannels in Glia: Neuronal Network Regulation

多胺，精胺/亚精胺（SP/SD），在神经元活动期间从未知来源释放到全脑中。 活动SP/SD显著改变神经元网络，并对NMDA诱导的神经毒性具有神经保护作用， 缺血有趣的是，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。我们的初步 数据提示星形胶质细胞的SP/SD摄取和释放可能通过未贴壁的间隙连接（半通道）发生。 这一发现使我们提出了一个新的工作假设，即SP/SD在神经元中合成，并渗透到（i）连接蛋白 神经胶质中的半通道最终储存在神经胶质合胞体中。(ii)神经元兴奋导致短暂的跌落 [Ca2 +] 0和[H +] 0的增加以及[K +] 0的增加促进：（iii）神经胶质细胞中半通道的开放和（iv） SP从神经胶质到神经元环境，在那里它可以作用于AMPA、红藻氨酸和NMDA受体， 细胞外SP通过二价阳离子解除残留的半通道阻滞，因此SP作为正反馈信号， 胶质半通道。我们认为SP/SD是一种信号分子，是一种新的调节机制的基础。 神经元和神经胶质。此外，我们的初步实验表明，SP本身可能有助于半通道的畅通， 因此，神经元兴奋可触发级联反应，导致快速的半通道开放。在这里我们问：（一）什么是 SP渗透通过半通道在神经胶质细胞的机制，（ii）如何释放SP调节下生理 条件和（iii）什么是SP通量通过星形胶质细胞膜在皮质切片的功能后果 准备？这些问题将通过研究SP通过半通道运输的机制来解决， 检测SP对异源表达的Cx半通道的影响，并通过同时记录 中间神经元，星形胶质细胞和主细胞，同时确定半通道开放，SP 神经元兴奋性的释放和改变。这些研究将为理解新的 阐明了神经胶质细胞在调节神经元活动和减少K+扩散过程中神经元损伤中的作用 抑郁症中风和局部缺血

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.