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

Abstract

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, GABA_A 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.

Keywords: GABA; cellular information processing; magnesium ion; neuronal development; signal transduction.