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Mutation I810N in the alpha3 isoform of Na+,K+-ATPase causes impairments in the sodium pump and hyperexcitability in the CNS.

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 alpha3 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 alpha3 by transgenesis, which also rescued Na(+),K(+)-ATPase activity. Our findings reveal the functional significance of the Na(+),K(+)-ATPase alpha3 isoform in the control of epileptiform activity and seizure behavior.

Pubmed ID: 19666602


  • Clapcote SJ
  • Duffy S
  • Xie G
  • Kirshenbaum G
  • Bechard AR
  • Rodacker Schack V
  • Petersen J
  • Sinai L
  • Saab BJ
  • Lerch JP
  • Minassian BA
  • Ackerley CA
  • Sled JG
  • Cortez MA
  • Henderson JT
  • Vilsen B
  • Roder JC


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

August 18, 2009

Associated Grants


Mesh Terms

  • Animals
  • Base Sequence
  • COS Cells
  • Central Nervous System
  • Cercopithecus aethiops
  • Hippocampus
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Mutation
  • Seizures
  • Sequence Homology, Nucleic Acid
  • Sodium-Potassium-Exchanging ATPase