1 Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA.
2 Departments of Neurology and Pediatrics, New York Medical College, Valhalla, NY, USA.
ASN Neuro. 2019 Jan-Dec;11:1759091419833502. doi: 10.1177/1759091419833502.
ATP- and adenosine-mediated signaling are prominent types of glia-glia and glia-neuron interaction, with an imbalance of ATP/adenosine ratio leading to altered states of excitability, as seen in epileptic seizures. Pannexin1 (Panx1), a member of the gap junction family, is an ATP release channel that is expressed in astrocytes and neurons. Previous studies provided evidence supporting a role for purinergic-mediated signaling via Panx1 channels in seizures; using mice with global deletion of Panx1, it was shown that these channels contribute in maintenance of seizures by releasing ATP. However, nothing is known about the extent to which astrocyte and neuronal Panx1 might differently contribute to seizures. We here show that targeted deletion of Panx1 in astrocytes or neurons has opposing effects on acute seizures induced by kainic acid. The absence of Panx1 in astrocytes potentiates while the absence of Panx1 in neurons attenuates seizure manifestation. Immunohistochemical analysis performed in brains of these mice, revealed that adenosine kinase (ADK), an enzyme that regulates extracellular levels of adenosine, was increased only in seized GFAP-Cre:Panx1 mice. Pretreating mice with the ADK inhibitor, idotubercidin, improved seizure outcome and prevented the increase in ADK immunoreactivity. Together, these data suggest that the worsening of seizures seen in mice lacking astrocyte Panx1 is likely related to low levels of extracellular adenosine due to the increased ADK levels in astrocytes. Our study not only reveals an unexpected link between Panx1 channels and ADK but also highlights the important role played by astrocyte Panx1 channels in controlling neuronal activity.
三磷酸腺苷（ATP）和腺苷介导的信号转导是胶质细胞-胶质细胞和胶质细胞-神经元相互作用的主要类型，ATP/腺苷比值的失衡导致兴奋性改变，如癫痫发作中所见。连接蛋白 1（Panx1）是间隙连接家族的成员，是一种在星形胶质细胞和神经元中表达的 ATP 释放通道。先前的研究提供了证据，支持嘌呤能介导的信号转导通过 Panx1 通道在癫痫发作中的作用；使用 Panx1 全局缺失的小鼠表明，这些通道通过释放 ATP 有助于维持癫痫发作。然而，对于星形胶质细胞和神经元 Panx1 可能在多大程度上不同地参与癫痫发作，目前还一无所知。我们在这里表明，星形胶质细胞或神经元中 Panx1 的靶向缺失对红藻氨酸诱导的急性癫痫发作有相反的影响。星形胶质细胞中 Panx1 的缺失增强了而神经元中 Panx1 的缺失则减弱了癫痫发作的表现。对这些小鼠大脑进行免疫组织化学分析显示，调节细胞外腺苷水平的酶腺苷激酶（ADK）仅在 GFAP-Cre:Panx1 小鼠中增加。用 ADK 抑制剂碘代尿苷预先处理小鼠可改善癫痫发作结果并防止 ADK 免疫反应性增加。总之，这些数据表明，缺乏星形胶质细胞 Panx1 的小鼠癫痫发作恶化可能与由于星形胶质细胞中 ADK 水平升高导致的细胞外腺苷水平降低有关。我们的研究不仅揭示了 Panx1 通道和 ADK 之间的意外联系，还强调了星形胶质细胞 Panx1 通道在控制神经元活动中的重要作用。
