TRPM2 enhances ischemic excitotoxicity by associating with PKCγ

Zong, Pengyu; Feng, Jianlin; Legere, Nicholas; Li, Yunfeng; Yue, Zhichao; Li, Cindy X.; Mori, Yasuo; Miller, Barbara; Hao, Bing; Yue, Lixia

doi:10.1016/j.celrep.2024.113722

Cell Reports

2024

DOI: 10.1016/j.celrep.2024.113722

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TRPM2 enhances ischemic excitotoxicity by associating with PKCγ

Pengyu Zong,

Jianlin Feng,

Nicholas Legere

et al.

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Cited by 4 publications

References 53 publications

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NMDA Receptor–Mediated Ca²⁺ Flux Attenuated by the NMDA Receptor/TRPM4 Interface Inhibitor Brophenexin

Casby,

Gansemer,

Thayer

2024

Pharmacology Res & Perspec

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Transient receptor potential melastatin‐4 (TRPM4) forms a complex with N‐methyl‐D‐aspartate receptors (NMDARs) that facilitates NMDAR‐mediated neurotoxicity. Here we used pharmacological tools to determine how TRPM4 regulates NMDAR signaling. Brophenexin, a compound that binds to TRPM4 at the NMDAR binding interface, protected hippocampal neurons in culture from NMDA‐induced death, consistent with published work. Brophenexin (10 μM) reduced NMDA‐evoked whole‐cell currents recorded at 22°C by 87% ± 14% with intracellular Ca2+ chelated to prevent TRPM4 activation. Brophenexin inhibited NMDA‐evoked currents recorded in Na+‐free solution by 87% ± 13%, suggesting that brophenexin and TRPM4 modulate NMDAR function. Incubating cultures in Mg2+‐free buffer containing tetrodotoxin, 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione, and bicuculline for 30 min inhibited NMDA‐evoked increases in intracellular Ca2+ concentration ([Ca2+]i) recorded at 22°C by 50% ± 18% and prevented inhibition by brophenexin. In the absence of these inhibitors, brophenexin inhibited the NMDA‐evoked response by 51% ± 16%. Treatment with the TRPM4 inhibitor 4‐chloro‐2‐(1‐naphthyloxyacetamido)benzoic acid (NBA; 10 μM) increased NMDA‐evoked Ca2+ influx by 90% ± 15%. Increasing extracellular NaCl to 237 mM, a treatment that activates TRPM4, inhibited the NMDA‐evoked increase in [Ca2+]i by a process that occluded the inhibition produced by brophenexin and was prevented by NBA. In recordings performed at 32°C–34°C, brophenexin inhibited the NMDA‐evoked [Ca2+]i response by 42% ± 10% but NBA was without effect. These results are consistent with a model in which TRPM4 interacts with NMDARs to potentiate Ca2+ flux through the NMDAR ion channel and thus provides a potential mechanism for the neuroprotection afforded by NMDAR/TRPM4 interface inhibitors such as brophenexin.

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NMDA Receptor–Mediated Ca²⁺ Flux Attenuated by the NMDA Receptor/TRPM4 Interface Inhibitor Brophenexin

Casby,

Gansemer,

Thayer

2024

Pharmacology Res & Perspec

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show abstract

From oxidative stress to metabolic dysfunction: The role of TRPM2

Li,

Ren,

et al. 2025

International Journal of Biological Macromolecules

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TRP Channels in Excitotoxicity

Zong,

Legere,

Feng

et al. 2024

Neuroscientist

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Glutamate excitotoxicity is a central mechanism contributing to cellular dysfunction and death in various neurological disorders and diseases, such as stroke, traumatic brain injury, epilepsy, schizophrenia, addiction, mood disorders, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, pathologic pain, and even normal aging-related changes. This detrimental effect emerges from glutamate binding to glutamate receptors, including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, N-methyl-d-aspartate receptors, kainate receptors, and GluD receptors. Thus, excitotoxicity could be prevented by targeting glutamate receptors and their downstream signaling pathways. However, almost all the glutamate receptor antagonists failed to attenuate excitotoxicity in human patients, mainly due to the limited understanding of the underlying mechanisms regulating excitotoxicity. Transient receptor potential (TRP) channels serve as ancient cellular sensors capable of detecting and responding to both external and internal stimuli. The study of human TRP channels has flourished in recent decades since the initial discovery of mammalian TRP in 1995. These channels have been found to play pivotal roles in numerous pathologic conditions, including excitotoxicity. In this review, our focus centers on exploring the intricate interactions between TRP channels and glutamate receptors in excitotoxicity.

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TRPM2 enhances ischemic excitotoxicity by associating with PKCγ

Cited by 4 publications

References 53 publications

NMDA Receptor–Mediated Ca²⁺ Flux Attenuated by the NMDA Receptor/TRPM4 Interface Inhibitor Brophenexin

NMDA Receptor–Mediated Ca²⁺ Flux Attenuated by the NMDA Receptor/TRPM4 Interface Inhibitor Brophenexin

From oxidative stress to metabolic dysfunction: The role of TRPM2

TRP Channels in Excitotoxicity

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Product

Resources

About

TRPM2 enhances ischemic excitotoxicity by associating with PKCγ

Cited by 4 publications

References 53 publications

NMDA Receptor–Mediated Ca2+ Flux Attenuated by the NMDA Receptor/TRPM4 Interface Inhibitor Brophenexin

NMDA Receptor–Mediated Ca2+ Flux Attenuated by the NMDA Receptor/TRPM4 Interface Inhibitor Brophenexin

From oxidative stress to metabolic dysfunction: The role of TRPM2

TRP Channels in Excitotoxicity

Contact Info

Product

Resources

About

NMDA Receptor–Mediated Ca²⁺ Flux Attenuated by the NMDA Receptor/TRPM4 Interface Inhibitor Brophenexin

NMDA Receptor–Mediated Ca²⁺ Flux Attenuated by the NMDA Receptor/TRPM4 Interface Inhibitor Brophenexin