RRC ID 21528
Author 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.
Title Mutation I810N in the alpha3 isoform of Na+,K+-ATPase causes impairments in the sodium pump and hyperexcitability in the CNS.
Journal Proc. Natl. Acad. Sci. U.S.A.
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.
Volume 106(33)
Pages 14085-90
Published 2009-8-18
DOI 10.1073/pnas.0904817106
PII 0904817106
PMID 19666602
PMC PMC2729024
MeSH Animals Base Sequence COS Cells Central Nervous System / metabolism* Cercopithecus aethiops Hippocampus / metabolism Male Mice Mice, Inbred C57BL Molecular Sequence Data Mutation* Seizures / genetics Seizures / pathology Sequence Homology, Nucleic Acid Sodium-Potassium-Exchanging ATPase / genetics Sodium-Potassium-Exchanging ATPase / metabolism*
IF 9.504
Times Cited 68
DNA material MSM Mouse BAC (RDB04214) MSMg01–344N17