Importance of Pannexin to Astrocyte and Neuronal ATP

Pannexin 对星形胶质细胞和神经元 ATP 的重要性

• 批准号: 9260940
• 负责人: Eliana Scemes
• 金额: $ 32.41万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2017-11-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260940
• 关键词: Affect; Applications Grants; Astrocytes; Behavior monitoring; Biological; Biological Assay; Brain; Calcium Signaling; Cell Communication; Cell membrane; Cells; Clinical; Communication; Connexins; Disease; Dyes; Electrophysiology (science); Epilepsy; Event; Gap Junctions; Goals; Hippocampus (Brain); Hyperactive behavior; In Situ; Inflammasome; Invertebrates; Ion Channel; Knockout Mice; Mechanics; Mediating; Metabolic; Microcirculation; Molecular; Monitor; Mus; Mutagenesis; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuroglia; Neurons; Orthologous Gene; Paracrine Communication; Peptides; Permeability; Pharmacology; Physiological; Play; Process; Reporting; Role; Seizures; Signal Transduction; Signaling Molecule; Site; Slice; Status Epilepticus; Stretching; Synapses; Therapeutic Intervention; Time; Transgenic Animals; Transgenic Mice; Wild Type Mouse; biophysical properties; cell injury; cell type; design; experimental study; extracellular; in vivo; insight; mutant; neuroinflammation; neuron loss; public health relevance; receptor; response; tool; transmission process; uptake; voltage

 DESCRIPTION (provided by applicant): Astrocytes interact with all types of neural cells by establishing direct cell-cell contacts through gap junctions and/or by releasing gliotransmitters which modulate synaptic activity, brain microcirculation, as well as neuroinflammatory and metabolic responses. Among the various types of paracrine signals, purinergic ATP-mediated signaling is emerging as the most prominent mechanism by which astrocytes interact among themselves and with neurons. This is because neural cells release and respond to ATP. ATP release from cells occurs through distinct mechanisms including ion channels. Recently, Pannexin1 (Panx1), a vertebrate ortholog of invertebrate gap junction protein, was found to form channels that we and others have proposed to be the site for ATP release. Pannexins are abundantly expressed in the CNS, both in glia and neurons, where they have been implicated in ischemic neuronal death and epileptiform activity. In concordance with the proposed role of Panx1 channels in hyperactivity, we recently found, using two different mouse lines with global Panx1 deletion that ATP release through these channels contributes to prolong the clinical manifestations of status epilepticus. A main question that remains to be answered, however, regards the cell type (astrocyte or neuron) that contributes to Panx1-mediated seizures. Thus, the overall aim of this grant application is to determine key missing information regarding cell-cell communication via Pannexin1 channels in the CNS, including the biophysical properties of these channels and the signal transduction events both leading to and resulting from Panx1 activation. For that we will use newly available conditional Panx1-null mice to directly evaluate the extent to which astrocyte or neuronal Panx1 channels contribute to status epilepticus by releasing ATP and to provide new mechanistic understanding of gating and signal transduction events of this new type of channel.

 描述（由适用提供）：星形胶质细胞通过通过间隙连接和/或释放胶质传递剂来建立直接的细胞 - 细胞接触来与所有类型的神经元细胞相互作用，从而调节合成活性，脑微循环以及神经衰减和代谢反应。在各种类型的旁分泌信号中，嘌呤能ATP介导的信号传导正在成为星形胶质细胞之间以及与神经元相互作用的最突出的机制。这是因为神经元细胞释放并响应ATP。从细胞中释放ATP是通过包括离子通道在内的不同机制发生的。最近，发现无脊椎动物间隙连接蛋白的Pannexin1（Panx1）是我们和其他人建议作为ATP释放的位点的通道。 Pannexin在中枢神经系统中绝对表达，无论是在神经元和神经元中，在缺血性神经元死亡和癫痫样活性中已实施。与PANX1通道在多动症中提出的作用一致，我们最近发现，使用具有全局PANX1缺失的两种不同的小鼠线，ATP通过这些通道释放有助于延长状态癫痫持续状态的临床表现。然而，尚待回答的一个主要问题涉及导致PANX1介导的癫痫发作的细胞类型（星形胶质细胞或神经元）。这是该赠款应用程序的总体目的是确定通过中枢神经系统中的Pannexin1通道的细胞细胞通信的关键信息，包括这些通道的生物物理特性和信号转导事件，均导致PANX1激活导致和导致。为此，我们将使用新近可用的条件panx1-null小鼠直接评估星形胶质细胞或神经元PANX1通道在多大程度上通过释放ATP并提供对这种新型通道的门控和信号传输事件的新机械理解来促进状态癫痫症的程度。