Epilepsy-Related Slack Channel Mutants Lead to Channel Over-Activity by Two Different Mechanisms
Twelve sodium-activated potassium channel (KCNT1, Slack) genetic mutants have been identified from severe early-onset epilepsy patients. The changes in biophysical properties of these mutants and the underlying mechanisms causing disease remain elusive. Here, we report that seven of the 12 mutations...
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| Format: | Article |
| Language: | English |
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Elsevier
2016-01-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124715014321 |
| _version_ | 1818486583844667392 |
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| author | Qiong-Yao Tang Fei-Fei Zhang Jie Xu Ran Wang Jian Chen Diomedes E. Logothetis Zhe Zhang |
| author_facet | Qiong-Yao Tang Fei-Fei Zhang Jie Xu Ran Wang Jian Chen Diomedes E. Logothetis Zhe Zhang |
| author_sort | Qiong-Yao Tang |
| collection | DOAJ |
| description | Twelve sodium-activated potassium channel (KCNT1, Slack) genetic mutants have been identified from severe early-onset epilepsy patients. The changes in biophysical properties of these mutants and the underlying mechanisms causing disease remain elusive. Here, we report that seven of the 12 mutations increase, whereas one mutation decreases, the channel’s sodium sensitivity. Two of the mutants exhibit channel over-activity only when the intracellular Na+ ([Na+]i) concentration is ∼80 mM. In contrast, single-channel data reveal that all 12 mutants increase the maximal open probability (Po). We conclude that these mutant channels lead to channel over-activity predominantly by increasing the ability of sodium binding to activate the channel, which is indicated by its maximal Po. The sodium sensitivity of these epilepsy causing mutants probably determines the [Na+]i concentration at which these mutants exert their pathological effects. |
| first_indexed | 2024-12-10T16:24:56Z |
| format | Article |
| id | doaj.art-78cba9e9e06f47f2bfdb4eb819184791 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T16:24:56Z |
| publishDate | 2016-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-78cba9e9e06f47f2bfdb4eb8191847912022-12-22T01:41:42ZengElsevierCell Reports2211-12472016-01-0114112913910.1016/j.celrep.2015.12.019Epilepsy-Related Slack Channel Mutants Lead to Channel Over-Activity by Two Different MechanismsQiong-Yao Tang0Fei-Fei Zhang1Jie Xu2Ran Wang3Jian Chen4Diomedes E. Logothetis5Zhe Zhang6Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu Province 221004, ChinaJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu Province 221004, ChinaJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu Province 221004, ChinaSchool of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu Province 221004, ChinaSchool of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu Province 221004, ChinaDepartment of Physiology and Biophysics, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USAJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu Province 221004, ChinaTwelve sodium-activated potassium channel (KCNT1, Slack) genetic mutants have been identified from severe early-onset epilepsy patients. The changes in biophysical properties of these mutants and the underlying mechanisms causing disease remain elusive. Here, we report that seven of the 12 mutations increase, whereas one mutation decreases, the channel’s sodium sensitivity. Two of the mutants exhibit channel over-activity only when the intracellular Na+ ([Na+]i) concentration is ∼80 mM. In contrast, single-channel data reveal that all 12 mutants increase the maximal open probability (Po). We conclude that these mutant channels lead to channel over-activity predominantly by increasing the ability of sodium binding to activate the channel, which is indicated by its maximal Po. The sodium sensitivity of these epilepsy causing mutants probably determines the [Na+]i concentration at which these mutants exert their pathological effects.http://www.sciencedirect.com/science/article/pii/S2211124715014321 |
| spellingShingle | Qiong-Yao Tang Fei-Fei Zhang Jie Xu Ran Wang Jian Chen Diomedes E. Logothetis Zhe Zhang Epilepsy-Related Slack Channel Mutants Lead to Channel Over-Activity by Two Different Mechanisms Cell Reports |
| title | Epilepsy-Related Slack Channel Mutants Lead to Channel Over-Activity by Two Different Mechanisms |
| title_full | Epilepsy-Related Slack Channel Mutants Lead to Channel Over-Activity by Two Different Mechanisms |
| title_fullStr | Epilepsy-Related Slack Channel Mutants Lead to Channel Over-Activity by Two Different Mechanisms |
| title_full_unstemmed | Epilepsy-Related Slack Channel Mutants Lead to Channel Over-Activity by Two Different Mechanisms |
| title_short | Epilepsy-Related Slack Channel Mutants Lead to Channel Over-Activity by Two Different Mechanisms |
| title_sort | epilepsy related slack channel mutants lead to channel over activity by two different mechanisms |
| url | http://www.sciencedirect.com/science/article/pii/S2211124715014321 |
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