The SWELL1 Channel Promotes Ischemic Brain Damage by Mediating Neuronal Swelling and Glutamate Toxicity
Abstract Cytotoxic neuronal swelling and glutamate excitotoxicity are two hallmarks of ischemic stroke. However, the underlying molecular mechanisms are not well understood. Here, it is reported that SWELL1, the essential subunit of the volume‐regulated anion channel (VRAC), plays a dual role in isc...
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| Format: | Article |
| Language: | English |
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Wiley
2024-09-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202401085 |
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| author | Jianan Chen Junhua Yang Jiachen Chu Kevin Hong Chen Jesse Alt Rana Rais Zhaozhu Qiu |
| author_facet | Jianan Chen Junhua Yang Jiachen Chu Kevin Hong Chen Jesse Alt Rana Rais Zhaozhu Qiu |
| author_sort | Jianan Chen |
| collection | DOAJ |
| description | Abstract Cytotoxic neuronal swelling and glutamate excitotoxicity are two hallmarks of ischemic stroke. However, the underlying molecular mechanisms are not well understood. Here, it is reported that SWELL1, the essential subunit of the volume‐regulated anion channel (VRAC), plays a dual role in ischemic injury by promoting neuronal swelling and glutamate excitotoxicity. SWELL1 expression is upregulated in neurons and astrocytes after experimental stroke in mice. The neuronal SWELL1 channel is activated by intracellular hypertonicity, leading to Cl− influx‐dependent cytotoxic neuronal swelling and subsequent cell death. Additionally, the SWELL1 channel in astrocytes mediates pathological glutamate release, indicated by increases in neuronal slow inward current frequency and tonic NMDAR current. Pharmacologically, targeting VRAC with a new inhibitor, an FDA‐approved drug Dicumarol, attenuated cytotoxic neuronal swelling and cell death, reduced astrocytic glutamate release, and provided significant neuroprotection in mice when administered either before or after ischemia. Therefore, these findings uncover the pleiotropic effects of the SWELL1 channel in neurons and astrocytes in the pathogenesis of ischemic stroke and provide proof of concept for therapeutically targeting it in this disease. |
| format | Article |
| id | doaj-art-b04777ce0b024b0b980dc3b894dbc7b9 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-09-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj-art-b04777ce0b024b0b980dc3b894dbc7b92025-08-20T01:55:09ZengWileyAdvanced Science2198-38442024-09-011136n/an/a10.1002/advs.202401085The SWELL1 Channel Promotes Ischemic Brain Damage by Mediating Neuronal Swelling and Glutamate ToxicityJianan Chen0Junhua Yang1Jiachen Chu2Kevin Hong Chen3Jesse Alt4Rana Rais5Zhaozhu Qiu6Department of Physiology Johns Hopkins University School of Medicine Baltimore MD 21205 USADepartment of Physiology Johns Hopkins University School of Medicine Baltimore MD 21205 USADepartment of Physiology Johns Hopkins University School of Medicine Baltimore MD 21205 USADepartment of Physiology Johns Hopkins University School of Medicine Baltimore MD 21205 USAJohns Hopkins Drug Discovery Johns Hopkins University School of Medicine Baltimore MD 21205 USAJohns Hopkins Drug Discovery Johns Hopkins University School of Medicine Baltimore MD 21205 USADepartment of Physiology Johns Hopkins University School of Medicine Baltimore MD 21205 USAAbstract Cytotoxic neuronal swelling and glutamate excitotoxicity are two hallmarks of ischemic stroke. However, the underlying molecular mechanisms are not well understood. Here, it is reported that SWELL1, the essential subunit of the volume‐regulated anion channel (VRAC), plays a dual role in ischemic injury by promoting neuronal swelling and glutamate excitotoxicity. SWELL1 expression is upregulated in neurons and astrocytes after experimental stroke in mice. The neuronal SWELL1 channel is activated by intracellular hypertonicity, leading to Cl− influx‐dependent cytotoxic neuronal swelling and subsequent cell death. Additionally, the SWELL1 channel in astrocytes mediates pathological glutamate release, indicated by increases in neuronal slow inward current frequency and tonic NMDAR current. Pharmacologically, targeting VRAC with a new inhibitor, an FDA‐approved drug Dicumarol, attenuated cytotoxic neuronal swelling and cell death, reduced astrocytic glutamate release, and provided significant neuroprotection in mice when administered either before or after ischemia. Therefore, these findings uncover the pleiotropic effects of the SWELL1 channel in neurons and astrocytes in the pathogenesis of ischemic stroke and provide proof of concept for therapeutically targeting it in this disease.https://doi.org/10.1002/advs.202401085cytotoxic neuronal swellingdicumarolglutamate excitotoxicityischemic strokeSWELL1 channels |
| spellingShingle | Jianan Chen Junhua Yang Jiachen Chu Kevin Hong Chen Jesse Alt Rana Rais Zhaozhu Qiu The SWELL1 Channel Promotes Ischemic Brain Damage by Mediating Neuronal Swelling and Glutamate Toxicity Advanced Science cytotoxic neuronal swelling dicumarol glutamate excitotoxicity ischemic stroke SWELL1 channels |
| title | The SWELL1 Channel Promotes Ischemic Brain Damage by Mediating Neuronal Swelling and Glutamate Toxicity |
| title_full | The SWELL1 Channel Promotes Ischemic Brain Damage by Mediating Neuronal Swelling and Glutamate Toxicity |
| title_fullStr | The SWELL1 Channel Promotes Ischemic Brain Damage by Mediating Neuronal Swelling and Glutamate Toxicity |
| title_full_unstemmed | The SWELL1 Channel Promotes Ischemic Brain Damage by Mediating Neuronal Swelling and Glutamate Toxicity |
| title_short | The SWELL1 Channel Promotes Ischemic Brain Damage by Mediating Neuronal Swelling and Glutamate Toxicity |
| title_sort | swell1 channel promotes ischemic brain damage by mediating neuronal swelling and glutamate toxicity |
| topic | cytotoxic neuronal swelling dicumarol glutamate excitotoxicity ischemic stroke SWELL1 channels |
| url | https://doi.org/10.1002/advs.202401085 |
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