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.
Clapcote
Steven J
SJ
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5. s.j.clapcote@leeds.ac.uk
Duffy
Steven
S
Xie
Gang
G
Kirshenbaum
Greer
G
Bechard
Allison R
AR
Rodacker Schack
Vivien
V
Petersen
Janne
J
Sinai
Laleh
L
Saab
Bechara J
BJ
Lerch
Jason P
JP
Minassian
Berge A
BA
Ackerley
Cameron A
CA
Sled
John G
JG
Cortez
Miguel A
MA
Henderson
Jeffrey T
JT
Vilsen
Bente
B
Roder
John C
JC
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*
C526097:Atp1a3 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase