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

被引：127

作者：

Clapcote, Steven J. ^{[1
,2
]}

Duffy, Steven ^{[2
]}

Xie, Gang ^{[2
]}

Kirshenbaum, Greer ^{[2
,3
,4
,5
,6
]}

Bechard, Allison R. ^{[2
]}

Schack, Vivien Rodacker ^{[7
]}

Petersen, Janne ^{[7
]}

Sinai, Laleh ^{[2
,3
,4
,5
,6
]}

Saab, Bechara J. ^{[2
,3
,4
,5
,6
]}

Lerch, Jason P. ^{[8
,9
,10
]}

Minassian, Berge A. ^{[3
,4
,5
,6
,8
,9
,10
]}

Ackerley, Cameron A. ^{[8
,9
,10
]}

Sled, John G. ^{[3
,4
,5
,6
,8
,9
,10
]}

Cortez, Miguel A. ^{[3
,4
,5
,6
,8
,9
,10
]}

Henderson, Jeffrey T. ^{[3
,4
,5
,6
]}

Vilsen, Bente ^{[7
]}

Roder, John C. ^{[2
,3
,4
,5
,6
]}

机构：

[1] Univ Leeds, Inst Membrane & Syst Biol, Leeds LS2 9JT, W Yorkshire, England

[2] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada

[3] Univ Toronto, Dept Med Biophys, Toronto, ON M5S 1A1, Canada

[4] Univ Toronto, Dept Med Genet, Toronto, ON M5S 1A1, Canada

[5] Univ Toronto, Dept Paediat, Toronto, ON M5S 1A1, Canada

[6] Univ Toronto, Dept Pharmaceut Sci, Toronto, ON M5S 1A1, Canada

[7] Univ Aarhus, Dept Physiol & Biophys, Ctr Membrane Pumps Cells & Dis PUMPKIN, Danish Natl Res Fdn, DK-8000 Aarhus, Denmark

[8] Hosp Sick Children, Mouse Imaging Ctr, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada

[9] Hosp Sick Children, Div Neurol, Toronto, ON M5G 1X8, Canada

[10] Hosp Sick Children, Div Pathol, Toronto, ON M5G 1X8, Canada

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 33期

基金：

英国医学研究理事会; 加拿大健康研究院; 新加坡国家研究基金会;

关键词：

alpha3; Na+; K+; ATPase; BAC rescue; epilepsy; forward genetic screen; mouse; ONSET DYSTONIA-PARKINSONISM; LONG-TERM DEPRESSION; K+-ATPASE; SEIZURES; NA; K-ATPASE; POTASSIUM; SUBUNIT; NA+; LOCALIZATION; MECHANISMS;

D O I：

10.1073/pnas.0904817106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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 alpha 3 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 alpha 3 by transgenesis, which also rescued Na+,K+-ATPase activity. Our findings reveal the functional significance of the Na+,K+-ATPase alpha 3 isoform in the control of epileptiform activity and seizure behavior.

引用

页码：14085 / 14090

页数：6

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