Journal
CELL REPORTS
Volume 14, Issue 1, Pages 129-139Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2015.12.019
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Funding
- Important Project of Natural Science in Colleges and Universities in Jiangsu Province [14KJA320002]
- Natural Science Foundation of China (NSFC) [81471314]
- NSFC [81450064]
- NIH [R01HL59949]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- Jiangsu Provincial Special Program of Medical Science [BL2014029]
- Training Programs of Innovation and Entrepreneurship for undergraduates of Jiangsu Province [201410313017Z]
- Training Programs of Innovation and Entrepreneurship for undergraduates of China [201410313017]
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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 similar to 80 mM. In contrast, single-channel data reveal that all 12 mutants increase the maximal open probability (P-o). 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 P-o. The sodium sensitivity of these epilepsy causing mutants probably determines the [Na+](i) concentration at which these mutants exert their pathological effects.
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