Mutation I810N in the α3 isoform of Na + ,K + -ATPase causes impairments in the sodium pump and hyperexcitability in the CNS
- 18 August 2009
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 106 (33) , 14085-14090
- https://doi.org/10.1073/pnas.0904817106
Abstract
In a mouse mutagenesis screen, we isolated a mutant, Myshkin (Myk), with autosomal dominant complex partial and secondarily generalized seizures, a greatly reduced threshold for hippocampal seizures in vitro, posttetanic hyperexcitability of the CA3-CA1 hippocampal pathway, and neuronal degeneration in the hippocampus. Positional cloning and functional analysis revealed that Myk/+ mice carry a mutation (I810N) which renders the normally expressed Na+,K+-ATPase α3 isoform inactive. Total Na+,K+-ATPase activity was reduced by 42% in Myk/+ brain. The epilepsy in Myk/+ mice and in vitro hyperexcitability could be prevented by delivery of additional copies of wild-type Na+,K+-ATPase α3 by transgenesis, which also rescued Na+,K+-ATPase activity. Our findings reveal the functional significance of the Na+,K+-ATPase α3 isoform in the control of epileptiform activity and seizure behavior.Keywords
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