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J. Biol. Chem., Vol. 281, Issue 10, 6273-6282, March 10, 2006
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From the
The Hotchkiss Brain Institute, Libin Cardiovascular Institute of Alberta, the Southern Alberta Cancer Research Institute, the ¶the Department of Biochemistry and Molecular Biology, and the ||Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta T2N 4N1, Canada, **The Psychiatric Institute, Departments of Psychiatry and Pharmacology, The University of Illinois, Chicago, Illinois 60612, and the Department of Ophthalmology & Visual Sciences, Dalhousie University, Halifax, Nova Scotia B3J 3G9, Canada
Plasma membrane Na+/Ca2+-exchangers play a predominant role in Ca2+ extrusion in brain. Neurons express several different Na+/Ca2+-exchangers belonging to both the K+-independent NCX family and the K+-dependent NCKX family. The unique contributions of each of these proteins to neuronal Ca2+ homeostasis and/or physiology remain largely unexplored. To address this question, we generated mice in which the gene encoding the abundant neuronal K+ -dependent Na+/Ca2+-exchanger protein, NCKX2, was knocked out. Analysis of these animals revealed a significant reduction in Ca2+ flux in cortical neurons, a profound loss of long term potentiation and an increase in long term depression at hippocampal Schaffer/CA1 synapses, and clear deficits in specific tests of motor learning and spatial working memory. Surprisingly, there was no obvious loss of photoreceptor function in cones, where expression of the NCKX2 protein had been reported previously. These data emphasize the critical and non-redundant role of NCKX2 in the local control of neuronal [Ca2+] that is essential for the development of synaptic plasticity associated with learning and memory.
Received for publication, November 11, 2005 , and in revised form, January 5, 2006.
* This work was supported in part by operating Grant MOP15035 from the Canadian Institutes of Health Research (CIHR) (to J. L.), by National Institutes of Health Grant NS37390 (to L. K.), and by a CIHR operating grant (to R. W. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Recipient of a CIHR Studentship.
2 A Scientist of the Alberta Heritage Foundation for Medical Research.
3 A Scholar of the Alberta Heritage Foundation for Medical Research.
4 Senior Scholars of the Alberta Heritage Foundation for Medical Research.
5 To whom correspondence should be addressed: University of Calgary Health Sciences Centre, Rm. 2518, 3330 Hospital Drive, NW, Calgary, Alberta T2N 4N1, Canada. Tel.: 403-220-2893; Fax: 403-283-4841; E-mail: jlytton{at}ucalgary.ca.
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