Activation of Calcium-Activated Chloride Channels Suppresses Inherited Seizure Susceptibility in Genetically Epilepsy-Prone Rats
Inherited seizure susceptibility in genetically epilepsy-prone rats (GEPR-3s) is associated with increased voltage-gated calcium channel currents suggesting a massive calcium influx resulting in increased levels of intraneuronal calcium. Cytosolic calcium, in turn, activates many processes, includin...
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| Format: | Article |
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MDPI AG
2022-02-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/10/2/449 |
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| author | Miracle Thomas Mark Simms Prosper N’Gouemo |
| author_facet | Miracle Thomas Mark Simms Prosper N’Gouemo |
| author_sort | Miracle Thomas |
| collection | DOAJ |
| description | Inherited seizure susceptibility in genetically epilepsy-prone rats (GEPR-3s) is associated with increased voltage-gated calcium channel currents suggesting a massive calcium influx resulting in increased levels of intraneuronal calcium. Cytosolic calcium, in turn, activates many processes, including chloride channels, to restore normal membrane excitability and limit repetitive firing of the neurons. Here we used EACT and T16Ainh-A01, potent activator and inhibitor of calcium-activated channels transmembrane protein 16A (TMEM16A), respectively, to probe the role of these channels in the pathophysiology of acoustically evoked seizures in the GEPR-3s. We used adult male and female GEPR-3s. Acoustically evoked seizures consisted of wild running seizures (WRSs) that evolved into generalized tonic-clonic seizures (GTCSs) and eventually culminated into forelimb extension (partial tonic seizures). We found that acute EACT treatment at relatively higher tested doses significantly reduced the incidences of WRSs and GTCSs, and the seizure severity in male GEPR-3s. Furthermore, these antiseizure effects were associated with delayed seizure onset and reduced seizure duration. Interestingly, the inhibition of TMEM16A channels reversed EACT’s antiseizure effects on seizure latency and seizure duration. No notable antiseizure effects were observed in female GEPR-3s. Together, these findings suggest that activation of TMEM16A channels may represent a putative novel cellular mechanism for suppressing GTCSs. |
| first_indexed | 2024-03-09T22:31:37Z |
| format | Article |
| id | doaj.art-2924f9ce683a43bb9e3eb17860dbdb9e |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-09T22:31:37Z |
| publishDate | 2022-02-01 |
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| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-2924f9ce683a43bb9e3eb17860dbdb9e2023-11-23T18:55:46ZengMDPI AGBiomedicines2227-90592022-02-0110244910.3390/biomedicines10020449Activation of Calcium-Activated Chloride Channels Suppresses Inherited Seizure Susceptibility in Genetically Epilepsy-Prone RatsMiracle Thomas0Mark Simms1Prosper N’Gouemo2Department of Physiology and Biophysics, Howard University College of Medicine, Washington, DC 20059, USADepartment of Physiology and Biophysics, Howard University College of Medicine, Washington, DC 20059, USADepartment of Physiology and Biophysics, Howard University College of Medicine, Washington, DC 20059, USAInherited seizure susceptibility in genetically epilepsy-prone rats (GEPR-3s) is associated with increased voltage-gated calcium channel currents suggesting a massive calcium influx resulting in increased levels of intraneuronal calcium. Cytosolic calcium, in turn, activates many processes, including chloride channels, to restore normal membrane excitability and limit repetitive firing of the neurons. Here we used EACT and T16Ainh-A01, potent activator and inhibitor of calcium-activated channels transmembrane protein 16A (TMEM16A), respectively, to probe the role of these channels in the pathophysiology of acoustically evoked seizures in the GEPR-3s. We used adult male and female GEPR-3s. Acoustically evoked seizures consisted of wild running seizures (WRSs) that evolved into generalized tonic-clonic seizures (GTCSs) and eventually culminated into forelimb extension (partial tonic seizures). We found that acute EACT treatment at relatively higher tested doses significantly reduced the incidences of WRSs and GTCSs, and the seizure severity in male GEPR-3s. Furthermore, these antiseizure effects were associated with delayed seizure onset and reduced seizure duration. Interestingly, the inhibition of TMEM16A channels reversed EACT’s antiseizure effects on seizure latency and seizure duration. No notable antiseizure effects were observed in female GEPR-3s. Together, these findings suggest that activation of TMEM16A channels may represent a putative novel cellular mechanism for suppressing GTCSs.https://www.mdpi.com/2227-9059/10/2/449acoustically evoked seizuresEACTgeneralized tonic-clonic seizuresinherited epilepsyTMEM1A channelswild running seizures |
| spellingShingle | Miracle Thomas Mark Simms Prosper N’Gouemo Activation of Calcium-Activated Chloride Channels Suppresses Inherited Seizure Susceptibility in Genetically Epilepsy-Prone Rats Biomedicines acoustically evoked seizures EACT generalized tonic-clonic seizures inherited epilepsy TMEM1A channels wild running seizures |
| title | Activation of Calcium-Activated Chloride Channels Suppresses Inherited Seizure Susceptibility in Genetically Epilepsy-Prone Rats |
| title_full | Activation of Calcium-Activated Chloride Channels Suppresses Inherited Seizure Susceptibility in Genetically Epilepsy-Prone Rats |
| title_fullStr | Activation of Calcium-Activated Chloride Channels Suppresses Inherited Seizure Susceptibility in Genetically Epilepsy-Prone Rats |
| title_full_unstemmed | Activation of Calcium-Activated Chloride Channels Suppresses Inherited Seizure Susceptibility in Genetically Epilepsy-Prone Rats |
| title_short | Activation of Calcium-Activated Chloride Channels Suppresses Inherited Seizure Susceptibility in Genetically Epilepsy-Prone Rats |
| title_sort | activation of calcium activated chloride channels suppresses inherited seizure susceptibility in genetically epilepsy prone rats |
| topic | acoustically evoked seizures EACT generalized tonic-clonic seizures inherited epilepsy TMEM1A channels wild running seizures |
| url | https://www.mdpi.com/2227-9059/10/2/449 |
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