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

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

Authors: Ryu Yamanaka, Yutaka Shindo, Kohji Hotta, Koji Suzuki, Kotaro Oka

Journal: Current Biology,Volume 28, Issue 24, P3984-3991.E5 (2018)

DOI:10.1016/j.cub.2018.10.044

Abstract:

Cells simultaneously utilize different intracellular signaling systems to process environmental information [1,2,3,4]. 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 [5,6,7,8,9,10,11]; 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 [15,16,17,18,19]. Here, we show that in neurons, GABA_Areceptor 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.