GABA-Induced Intracellular Mg2+ Mobilization Integrates and Coordinates Cellular Information Processing for the Maturation of Neural Networks
GABA-Induced Intracellular Mg2+ Mobilization Integrates and Coordinates Cellular Information Processing for the Maturation of Neural Networks
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DOI：
10.1016/j.cub.2018.10.044
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发表时间：
2018-12
期刊：
影响因子：
9.2
通讯作者：
Ryu Yamanaka;Yutaka Shindo;K. Hotta;Koji Suzuki;K. Oka
中科院分区：
文献类型：
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作者：
Ryu Yamanaka;Yutaka Shindo;K. Hotta;Koji Suzuki;K. Oka
细胞同时利用不同的细胞内信号系统来处理环境信息[1-4]。镁离子 (Mg2+) 被认为是一种多目标模拟调节剂，由于具有以下特性，可以发挥多种作用，例如昼夜节律计时：(1) 它影响广泛的生物过程，(2) 其浓度严格控制在狭窄的亚毫摩尔范围内，(3) 其细胞内动态缓慢且持久 [5-11]；与成熟的第二信使 Ca2+ 的类似开关信号转导相比，其调节方式不是全有或全无的[12]。然而，最近的研究报告了 Mg2+ 作为免疫细胞中第二信使的另一个作用，即细胞状态的转换系统 [13, 14]。 Mg2+ 的这些多方面特征提出了 Mg2+ 如何处理信息以及其作为信号分子的作用有多普遍的问题。我们重点关注γ-氨基丁酸（GABA）的营养作用及其发育转变，尽管其在进化上的作用非常保守，但其分子基础仍然知之甚少[15-19]。在这里，我们表明，在神经元中，GABAA 受体信号传导具有兴奋性，特别是在早期发育阶段触发线粒体释放 Mg2+，并且释放的 Mg2+ 刺激 CREB 和 mTOR 信号通路，从而促进神经网络的结构和功能成熟。我们发现生理范围内的胞质 Mg2+ 波动足以关键地调节 ERK、CREB 和 mTOR 活性。细胞内的 Mg2+ 在生理上整合和协调细胞信息，并且 Mg2+ 是一种用于组织神经网络的新型信号传感器。
Cells simultaneously utilize different intracellular signaling systems to process environmental information [1–4]. The magnesium ion (Mg2+) is recognized as a multitarget analog regulator that performs many roles, such as circadian timekeeping, due to the following properties: (1) it influences wide-ranging biological processes, (2) its concentration is tightly controlled within a narrow sub-millimolar range, and (3) its intracellular dynamics are slow and long lasting [5–11]; its regulatory manner is not all-or-none in contrast to the switch-like signal transduction by the well-established second messenger Ca2+[12]. Recent studies, however, have reported another role for Mg2+as a second messenger in immune cells—i.e., a switching system for cellular states [13, 14]. These multifaceted characteristics of Mg2+raise the question of how Mg2+processes information and how common its role is as a signaling molecule. We focused on the trophic effects of γ-aminobutyric acid (GABA) and its developmental transition, the molecular basis of which also remains poorly understood despite its evolutionarily well-conserved roles [15–19]. Here, we show that in neurons, GABAAreceptor signaling, whose action is excitatory, triggers Mg2+release from mitochondria specifically at early developmental stages, and that released Mg2+stimulates the CREB and mTOR signaling pathways, thereby facilitating structural and functional maturation of neural networks. We found that cytosolic Mg2+fluctuations within physiological ranges is enough to crucially regulate ERK, CREB, and mTOR activities. Together, intracellular Mg2+physiologically integrates and coordinates cellular information, and Mg2+is a novel signal transducer for organizing neural networks.