Open AccessMagnesium Acts as a Second Messenger in the Regulation of NMDA Receptor-Mediated CREB Signaling in Neurons
Author(s) -
Hailong Hou,
Liwei Wang,
Tianyue Fu,
Makaia Papasergi,
David I. Yule,
Houhui Xia
Publication year - 2020
Publication title -
molecular neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.569
H-Index - 111
eISSN - 1559-1182
pISSN - 0893-7648
DOI - 10.1007/s12035-020-01871-z
Subject(s) - creb , nmda receptor , extracellular , microbiology and biotechnology , signal transduction , mapk/erk pathway , intracellular , chemistry , protein kinase a , biology , receptor , neuroscience , kinase , biochemistry , transcription factor , gene
Extracellular magnesium ion ([Mg 2+ ]) is a well-known voltage-dependent blocker of NMDA receptors, which plays a critical role in the regulation of neuronal plasticity, learning, and memory. It is generally believed that NMDA receptor activation involves in Mg 2+ being removed into extracellular compartment from the channel pore. On the other hand, Mg 2+ is one of the most abundant intracellular cations, and involved in numerous cellular functions. However, we do not know if extracellular magnesium ions can influx into neurons to affect intracellular signaling pathways. In our current study, we found that extracellular [Mg 2+ ] elevation enhanced CREB activation by NMDA receptor signaling in both mixed sex rat cultured neurons and brain slices. Moreover, we found that extracellular [Mg 2+ ] led to CREB activation by NMDA application, albeit in a delayed manner, even in the absence of extracellular calcium, suggesting a potential independent role of magnesium in CREB activation. Consistent with this, we found that NMDA application leads to an NMDAR-dependent increase in intracellular-free [Mg 2+ ] in cultured neurons in the absence of extracellular calcium. Chelating this magnesium influx or inhibiting P38 mitogen-activated protein kinase (p38 MAPK) blocked the delayed pCREB by NMDA. Finally, we found that NMDAR signaling in the absence of extracellular calcium activates p38 MAPK. Our studies thus indicate that magnesium influx, dependent on NMDA receptor opening, can transduce a signaling pathway to activate CREB in neurons.