TRPM4 blocking antibody reduces neuronal excitotoxicity by specifically inhibiting glutamate-induced calcium influx under chronic hypoxia

Excitotoxicity arises from unusually excessive activation of excitatory amino acid receptors such as glutamate receptors. Following an energy crisis, excitotoxicity is a major cause for neuronal death in neurological disorders. Many glutamate antagonists have been examined for their efficacy in miti...

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Published in:Neurobiology of Disease
Main Author: Poore C.P.; Hazalin N.A.M.N.; Wei S.; Low S.W.; Chen B.; Nilius B.; Hassan Z.; Liao P.
Format: Article
Language:English
Published: Academic Press Inc. 2024
Online Access:https://www.scopus.com/inward/record.uri?eid=2-s2.0-85182873860&doi=10.1016%2fj.nbd.2024.106408&partnerID=40&md5=7c1fb1b993feb06eb855d715bacc3bfe
id 2-s2.0-85182873860
spelling 2-s2.0-85182873860
Poore C.P.; Hazalin N.A.M.N.; Wei S.; Low S.W.; Chen B.; Nilius B.; Hassan Z.; Liao P.
TRPM4 blocking antibody reduces neuronal excitotoxicity by specifically inhibiting glutamate-induced calcium influx under chronic hypoxia
2024
Neurobiology of Disease
191

10.1016/j.nbd.2024.106408
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85182873860&doi=10.1016%2fj.nbd.2024.106408&partnerID=40&md5=7c1fb1b993feb06eb855d715bacc3bfe
Excitotoxicity arises from unusually excessive activation of excitatory amino acid receptors such as glutamate receptors. Following an energy crisis, excitotoxicity is a major cause for neuronal death in neurological disorders. Many glutamate antagonists have been examined for their efficacy in mitigating excitotoxicity, but failed to generate beneficial outcome due to their side effects on healthy neurons where glutamate receptors are also blocked. In this study, we found that during chronic hypoxia there is upregulation and activation of a nonselective cation channel TRPM4 that contributes to the depolarized neuronal membrane potential and enhanced glutamate-induced calcium entry. TRPM4 is involved in modulating neuronal membrane excitability and calcium signaling, with a complex and multifaceted role in the brain. Here, we inhibited TRPM4 using a newly developed blocking antibody M4P, which could repolarize the resting membrane potential and ameliorate calcium influx upon glutamate stimulation. Importantly, M4P did not affect the functions of healthy neurons as the activity of TRPM4 channel is not upregulated under normoxia. Using a rat model of chronic hypoxia with both common carotid arteries occluded, we found that M4P treatment could reduce apoptosis in the neurons within the hippocampus, attenuate long-term potentiation impairment and improve the functions of learning and memory in this rat model. With specificity to hypoxic neurons, TRPM4 blocking antibody can be a novel way of controlling excitotoxicity with minimal side effects that are common among direct blockers of glutamate receptors. © 2023
Academic Press Inc.
9699961
English
Article
All Open Access; Gold Open Access
author Poore C.P.; Hazalin N.A.M.N.; Wei S.; Low S.W.; Chen B.; Nilius B.; Hassan Z.; Liao P.
spellingShingle Poore C.P.; Hazalin N.A.M.N.; Wei S.; Low S.W.; Chen B.; Nilius B.; Hassan Z.; Liao P.
TRPM4 blocking antibody reduces neuronal excitotoxicity by specifically inhibiting glutamate-induced calcium influx under chronic hypoxia
author_facet Poore C.P.; Hazalin N.A.M.N.; Wei S.; Low S.W.; Chen B.; Nilius B.; Hassan Z.; Liao P.
author_sort Poore C.P.; Hazalin N.A.M.N.; Wei S.; Low S.W.; Chen B.; Nilius B.; Hassan Z.; Liao P.
title TRPM4 blocking antibody reduces neuronal excitotoxicity by specifically inhibiting glutamate-induced calcium influx under chronic hypoxia
title_short TRPM4 blocking antibody reduces neuronal excitotoxicity by specifically inhibiting glutamate-induced calcium influx under chronic hypoxia
title_full TRPM4 blocking antibody reduces neuronal excitotoxicity by specifically inhibiting glutamate-induced calcium influx under chronic hypoxia
title_fullStr TRPM4 blocking antibody reduces neuronal excitotoxicity by specifically inhibiting glutamate-induced calcium influx under chronic hypoxia
title_full_unstemmed TRPM4 blocking antibody reduces neuronal excitotoxicity by specifically inhibiting glutamate-induced calcium influx under chronic hypoxia
title_sort TRPM4 blocking antibody reduces neuronal excitotoxicity by specifically inhibiting glutamate-induced calcium influx under chronic hypoxia
publishDate 2024
container_title Neurobiology of Disease
container_volume 191
container_issue
doi_str_mv 10.1016/j.nbd.2024.106408
url https://www.scopus.com/inward/record.uri?eid=2-s2.0-85182873860&doi=10.1016%2fj.nbd.2024.106408&partnerID=40&md5=7c1fb1b993feb06eb855d715bacc3bfe
description Excitotoxicity arises from unusually excessive activation of excitatory amino acid receptors such as glutamate receptors. Following an energy crisis, excitotoxicity is a major cause for neuronal death in neurological disorders. Many glutamate antagonists have been examined for their efficacy in mitigating excitotoxicity, but failed to generate beneficial outcome due to their side effects on healthy neurons where glutamate receptors are also blocked. In this study, we found that during chronic hypoxia there is upregulation and activation of a nonselective cation channel TRPM4 that contributes to the depolarized neuronal membrane potential and enhanced glutamate-induced calcium entry. TRPM4 is involved in modulating neuronal membrane excitability and calcium signaling, with a complex and multifaceted role in the brain. Here, we inhibited TRPM4 using a newly developed blocking antibody M4P, which could repolarize the resting membrane potential and ameliorate calcium influx upon glutamate stimulation. Importantly, M4P did not affect the functions of healthy neurons as the activity of TRPM4 channel is not upregulated under normoxia. Using a rat model of chronic hypoxia with both common carotid arteries occluded, we found that M4P treatment could reduce apoptosis in the neurons within the hippocampus, attenuate long-term potentiation impairment and improve the functions of learning and memory in this rat model. With specificity to hypoxic neurons, TRPM4 blocking antibody can be a novel way of controlling excitotoxicity with minimal side effects that are common among direct blockers of glutamate receptors. © 2023
publisher Academic Press Inc.
issn 9699961
language English
format Article
accesstype All Open Access; Gold Open Access
record_format scopus
collection Scopus
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