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Cited by 65Neuroscience and Neuropharmacology ResearchTreatment of Major DepressionAmino Acid Enzymes and Metabolism

Magnesium Acts as a Second Messenger in the Regulation of NMDA Receptor-Mediated CREB Signaling in Neurons

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Hou, Hailong, Wang, Liwei, Fu, Tianyue, Papasergi, Makaia, Yule, David I., Xia, Houhui·2020·Molecular Neurobiology
DOI 10.1007/s12035-020-01871-zPMC PMC8202957
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Abstract

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.

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  • These events culminate in excitotoxic neuronal death, particularly affecting vulnerable regions such as hippocampus and cortex.

    “Collectively, these events culminate in excitotoxic neuronal death, particularly affecting vulnerable regions such as the hippocampus and cortex.”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [117]

    The Introduction links extrasynaptic NMDA receptor signaling and CREB shut-off to glutamate toxicity in ischemic stroke. It does not state that the events culminate in neuronal death or that the hippocampus and cortex are particularly vulnerable; the Methods’ use of cortical neurons does not establish regional vulnerability. No page number is available in our copy. (LLM, conf=0.77)

    Experimental — accuracy not yet measured

  • In AD, overstimulation of NMDA receptors displaces Mg2+, resulting in uncontrolled influx of Ca2+ and Na+ ions.

    “In AD, however, this finely tuned system becomes dysregulated. Overstimulation of NMDA receptors displaces Mg2+, resulting in uncontrolled influx of Ca2+ and sodium (Na+) ions.”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [117]

    The Introduction and Discussion (page numbers unavailable) state that Mg2+ blocks NMDA receptors and that membrane depolarization can relieve the block. The Results report Ca2+ responses to NMDA in cultured neurons. The paper does not establish that, in Alzheimer’s disease, receptor overstimulation displaces Mg2+ or causes uncontrolled Ca2+ and Na+ influx. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Elevated intracellular Ca2+ activates deleterious processes including ROS generation, mitochondrial dysfunction, activation of proteases and endonucleases, and initiation of necrotic and apoptotic pathways.

    “Elevated intracellular Ca2+ activates a cascade of deleterious processes, including the generation of ROS, mitochondrial dysfunction, activation of proteases and endonucleases, and initiation of necrotic and apoptotic pathways [117].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [117]

    The Introduction discusses calcium-dependent CREB signaling and links extrasynaptic NMDA receptor signaling to glutamate toxicity, but does not describe the claimed calcium-triggered damage cascade. Searches for ROS, mitochondrial dysfunction, proteases, endonucleases, necrosis, and apoptosis found no passage in our copy supporting that cascade. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

  • Ca2+ overload exacerbates mitochondrial dysfunction, creating a vicious cycle of impaired bioenergetics and oxidative stress.

    “Ca2+ overload exacerbates mitochondrial dysfunction, creating a vicious cycle of impaired bioenergetics and oxidative stress [117].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [117]

    The Introduction discusses glutamate toxicity and CREB signaling, while the Discussion addresses magnesium- and calcium-dependent CREB activation. Our copy does not address whether Ca2+ overload worsens mitochondrial dysfunction or creates a cycle of impaired bioenergetics and oxidative stress (searched for mitochondrial dysfunction, oxidative stress, calcium overload, and reactive oxygen species). No page numbers were available in the indexed passages. (LLM, conf=0.73)

    Experimental — accuracy not yet measured

  • By selectively blocking pathological receptor activation while sparing physiological signaling, memantine mitigates excitotoxic damage and modestly improves cognitive symptoms.

    “By selectively blocking pathological receptor activation while sparing physiological signaling, memantine mitigates excitotoxic damage and modestly improves cognitive symptoms [117].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [117]

    The Introduction and Discussion describe magnesium’s effects on NMDA receptor signaling under physiological and strong-stimulation conditions. A search for memantine found no passage about its selectivity, protection against excitotoxic damage, or effects on cognitive symptoms. Page numbers were not available in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Hou, H., Wang, L., Fu, T., Papasergi, M., Yule, D. I., & Xia, H.
Affiliations
University of Rochester Medicine (US)
Corresponding author
Xia, Houhui
ORCID
Venue
Molecular Neurobiology
Publisher
Springer Science and Business Media LLC
Published
2020-03-25
Volume
57
Issue
6
Pages
2539-2550
ISSN
  • 0893-7648 (ISSN-L)
  • 1559-1182
DOI
10.1007/s12035-020-01871-z
PMC
PMC8202957
OpenAlex
W3013767292
Cited by
65
References
2
Citations by year
2026: 10 · 2025: 26 · 2024: 14 · 2023: 1 · 2022: 9 · 2021: 2 · 2020: 3
FWCI
1.70
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurobiology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Mental Health (R01 MH109719)
  • Division of Integrative Organismal Systems (IOS-1457336)
  • National Institutes of Health (R01 DE014756)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords
extracellular magnesium, NMDA receptor, CREB activation, magnesium influx, p38 MAPK, intracellular magnesium, calcium-independent signaling, neuroplasticity, second messengers, long-term potentiation
MeSH terms
Animals, Cells, Cultured, Cerebral Cortex, Female, Magnesium, Male, Neurons, Second Messenger Systems, Signal Transduction, Receptors, N-Methyl-D-Aspartate, N-Methylaspartate, Rats, Sprague-Dawley, Cyclic AMP Response Element-Binding Protein, Excitatory Amino Acid Antagonists, Rats

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