Mutation I810N in the α3 isoform of Na+,K +-ATPase causes impairments in the sodium pump and hyperexcitability in the CNS

Steven J. Clapcote, Steven Duffy, Gang Xie, Greer Kirshenbaum, Allison R. Bechard, Vivien Rodacker Schack, Janne Petersen, Laleh Sinai, Bechara J. Saab, Jason P. Lerch, Berge A. Minassian, Cameron A. Ackerley, John G. Sled, Miguel A. Cortez, Jeffrey T. Henderson, Bente Vilsen, John C. Roder

Research output: Contribution to journalArticle

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Abstract

In a mouse mutagenesis screen,weisolated 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.

Original languageEnglish (US)
Pages (from-to)14085-14090
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number33
DOIs
StatePublished - Aug 18 2009

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Sodium-Potassium-Exchanging ATPase
Protein Isoforms
Mutation
Seizures
Gene Transfer Techniques
Mutagenesis
Adenosine Triphosphatases
Organism Cloning
Epilepsy
Hippocampus
sodium-translocating ATPase
Brain
In Vitro Techniques

Keywords

  • Alpha3 Na,K ATPase
  • BAC rescue
  • Epilepsy
  • Forward genetic screen
  • Mouse

ASJC Scopus subject areas

  • General

Cite this

Mutation I810N in the α3 isoform of Na+,K +-ATPase causes impairments in the sodium pump and hyperexcitability in the CNS. / Clapcote, Steven J.; Duffy, Steven; Xie, Gang; Kirshenbaum, Greer; Bechard, Allison R.; Schack, Vivien Rodacker; Petersen, Janne; Sinai, Laleh; Saab, Bechara J.; Lerch, Jason P.; Minassian, Berge A.; Ackerley, Cameron A.; Sled, John G.; Cortez, Miguel A.; Henderson, Jeffrey T.; Vilsen, Bente; Roder, John C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 33, 18.08.2009, p. 14085-14090.

Research output: Contribution to journalArticle

Clapcote, SJ, Duffy, S, Xie, G, Kirshenbaum, G, Bechard, AR, Schack, VR, Petersen, J, Sinai, L, Saab, BJ, Lerch, JP, Minassian, BA, Ackerley, CA, Sled, JG, Cortez, MA, Henderson, JT, Vilsen, B & Roder, JC 2009, 'Mutation I810N in the α3 isoform of Na+,K +-ATPase causes impairments in the sodium pump and hyperexcitability in the CNS', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 33, pp. 14085-14090. https://doi.org/10.1073/pnas.0904817106
Clapcote, Steven J. ; Duffy, Steven ; Xie, Gang ; Kirshenbaum, Greer ; Bechard, Allison R. ; Schack, Vivien Rodacker ; Petersen, Janne ; Sinai, Laleh ; Saab, Bechara J. ; Lerch, Jason P. ; Minassian, Berge A. ; Ackerley, Cameron A. ; Sled, John G. ; Cortez, Miguel A. ; Henderson, Jeffrey T. ; Vilsen, Bente ; Roder, John C. / Mutation I810N in the α3 isoform of Na+,K +-ATPase causes impairments in the sodium pump and hyperexcitability in the CNS. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 33. pp. 14085-14090.
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abstract = "In a mouse mutagenesis screen,weisolated 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.",
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AU - Kirshenbaum, Greer

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AU - Sinai, Laleh

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AU - Lerch, Jason P.

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AU - Ackerley, Cameron A.

AU - Sled, John G.

AU - Cortez, Miguel A.

AU - Henderson, Jeffrey T.

AU - Vilsen, Bente

AU - Roder, John C.

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