GABA-Induced Intracellular Mg2+ Mobilization Integrates and Coordinates Cellular Information Processing for the Maturation of Neural Networks.

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, GABAA receptor 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.