Metabolic autocrine regulation of neurons involves cooperation among pannexin hemichannels, adenosine receptors, and KATP channels.
Metabolic autocrine regulation of neurons involves cooperation among pannexin hemichannels, adenosine receptors, and KATP channels.
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DOI：
10.1523/jneurosci.0055-10.2010
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发表时间：
2010-03-17
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影响因子：
--
通讯作者：
Masino SA
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文献类型：
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作者：
Kawamura M Jr;Ruskin DN;Masino SA
降低或限制血糖的代谢紊乱-如禁食或坚持生酮饮食-可显著减少癫痫发作。迄今为止，代谢改变和神经元活动减少之间的关键联系仍然未知。更一般地说，代谢变化伴随着许多中枢神经系统疾病，嘌呤ATP及其核心分子腺苷准备将细胞能量转化为改变的神经元活动。在这里，我们表明，非病理性的代谢变化诱导海马CA 3区锥体神经元兴奋性的嘌呤能自动调节。在足够的细胞内ATP的条件下，减少细胞外葡萄糖诱导泛连接蛋白-1半通道介导的ATP直接从CA 3神经元释放。这种细胞外ATP被去磷酸化为腺苷，激活神经元腺苷A1受体，并且出乎意料地通过ATP敏感性K+通道使神经元膜电位超极化。总之，这些数据描绘了一个自分泌调节神经元的兴奋性通过ATP和腺苷在海马体的一个易患癫痫的亚区，并提供了新的机制洞察之间的关系降低葡萄糖和癫痫发作阈值增加。通过建立神经元ATP释放通过泛连接蛋白半通道，和海马腺苷A1受体耦合到ATP敏感的K+通道，我们揭示了代谢和神经元活动之间的关系的详细信息和腺苷为基础的治疗在中枢神经系统的新策略。
Metabolic perturbations that decrease or limit blood glucose - such as fasting or adhering to a ketogenic diet – reduce epileptic seizures significantly. To date, the critical links between altered metabolism and decreased neuronal activity remain unknown. More generally, metabolic changes accompany numerous central nervous system disorders, and the purines ATP and its core molecule adenosine are poised to translate cell energy into altered neuronal activity. Here we show that non-pathological changes in metabolism induce a purinergic autoregulation of hippocampal CA3 pyramidal neuron excitability. During conditions of sufficient intracellular ATP, reducing extracellular glucose induces pannexin-1 hemichannel-mediated ATP release directly from CA3 neurons. This extracellular ATP is dephosphorylated to adenosine, activates neuronal adenosine A1 receptors, and, unexpectedly, hyperpolarizes neuronal membrane potential via ATP-sensitive K+ channels. Together, these data delineate an autocrine regulation of neuronal excitability via ATP and adenosine in a seizure-prone subregion of the hippocampus, and offer new mechanistic insight into the relationship between decreased glucose and increased seizure threshold. By establishing neuronal ATP release via pannexin hemichannels, and hippocampal adenosine A1 receptors coupled to ATP-sensitive K+ channels, we reveal detailed information regarding the relationship between metabolism and neuronal activity and new strategies for adenosine-based therapies in the central nervous system.