title: Mutation I810N in the alpha3 isoform of Na+,K+-ATPase causes impairments in the sodium pump and hyperexcitability in the CNS.
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 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.
authors: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5. s.j.clapcote@leeds.ac.uk
authors: Steven J
authors: SJ
authors: Clapcote
authors: Steven
authors: S
authors: Duffy
authors: Gang
authors: G
authors: Xie
authors: Greer
authors: G
authors: Kirshenbaum
authors: Allison R
authors: AR
authors: Bechard
authors: Vivien
authors: V
authors: Rodacker Schack
authors: Janne
authors: J
authors: Petersen
authors: Laleh
authors: L
authors: Sinai
authors: Bechara J
authors: BJ
authors: Saab
authors: Jason P
authors: JP
authors: Lerch
authors: Berge A
authors: BA
authors: Minassian
authors: Cameron A
authors: CA
authors: Ackerley
authors: John G
authors: JG
authors: Sled
authors: Miguel A
authors: MA
authors: Cortez
authors: Jeffrey T
authors: JT
authors: Henderson
authors: Bente
authors: B
authors: Vilsen
authors: John C
authors: JC
authors: Roder
mesh_terms: D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002490:Central Nervous System / Q000378:metabolism*; D002522:Chlorocebus aethiops; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D012640:Seizures / Q000235:genetics / Q000473:pathology; D012689:Sequence Homology, Nucleic Acid; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism*
chemical_list: C526097:Atp1a3 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase