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 Authors: Poore, Charlene P.; Hazalin, Nurul A. M. N.; Wei, Shunhui; Low, See Wee; Chen, Bo; Nilius, Bernd; Hassan, Zurina; Liao, Ping
Format: Article
Language:English
Published: ACADEMIC PRESS INC ELSEVIER SCIENCE 2024
Subjects:
Online Access:https://www-webofscience-com.uitm.idm.oclc.org/wos/woscc/full-record/WOS:001166358900001
author Poore
Charlene P.; Hazalin
Nurul A. M. N.; Wei
Shunhui; Low
See Wee; Chen
Bo; Nilius
Bernd; Hassan
Zurina; Liao
Ping
spellingShingle Poore
Charlene P.; Hazalin
Nurul A. M. N.; Wei
Shunhui; Low
See Wee; Chen
Bo; Nilius
Bernd; Hassan
Zurina; Liao
Ping
TRPM4 blocking antibody reduces neuronal excitotoxicity by specifically inhibiting glutamate-induced calcium influx under chronic hypoxia
Neurosciences & Neurology
author_facet Poore
Charlene P.; Hazalin
Nurul A. M. N.; Wei
Shunhui; Low
See Wee; Chen
Bo; Nilius
Bernd; Hassan
Zurina; Liao
Ping
author_sort Poore
spelling Poore, Charlene P.; Hazalin, Nurul A. M. N.; Wei, Shunhui; Low, See Wee; Chen, Bo; Nilius, Bernd; Hassan, Zurina; Liao, Ping
TRPM4 blocking antibody reduces neuronal excitotoxicity by specifically inhibiting glutamate-induced calcium influx under chronic hypoxia
NEUROBIOLOGY OF DISEASE
English
Article
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.
ACADEMIC PRESS INC ELSEVIER SCIENCE
0969-9961
1095-953X
2024
191

10.1016/j.nbd.2024.106408
Neurosciences & Neurology
gold
WOS:001166358900001
https://www-webofscience-com.uitm.idm.oclc.org/wos/woscc/full-record/WOS:001166358900001
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
container_title NEUROBIOLOGY OF DISEASE
language English
format Article
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.
publisher ACADEMIC PRESS INC ELSEVIER SCIENCE
issn 0969-9961
1095-953X
publishDate 2024
container_volume 191
container_issue
doi_str_mv 10.1016/j.nbd.2024.106408
topic Neurosciences & Neurology
topic_facet Neurosciences & Neurology
accesstype gold
id WOS:001166358900001
url https://www-webofscience-com.uitm.idm.oclc.org/wos/woscc/full-record/WOS:001166358900001
record_format wos
collection Web of Science (WoS)
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