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The Journal of Neuroscience, February 27, 2008, 28(9):2053-2063; doi:10.1523/JNEUROSCI.4912-07.2008

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Neurobiology of Disease
A Critical Role for the Potassium-Dependent Sodium–Calcium Exchanger NCKX2 in Protection against Focal Ischemic Brain Damage

Ornella Cuomo,¹ Rosaria Gala,¹ Giuseppe Pignataro,¹ Francesca Boscia,¹ Agnese Secondo,¹ Antonella Scorziello,¹ Anna Pannaccione,¹ Davide Viggiano,¹ Annagrazia Adornetto,¹ Pasquale Molinaro,¹ Xiao-Fang Li,² Jonathan Lytton,² Gianfranco Di Renzo,¹ and Lucio Annunziato¹

¹Division of Pharmacology, Department of Neuroscience, School of Medicine, "Federico II" University of Naples, 80131 Naples, Italy, and ²Department of Biochemistry and Molecular Biology, Libin Cardiovascular Institute of Alberta and the Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada T2N 4N1

Correspondence should be addressed to Dr. Lucio Annunziato, Division of Pharmacology, Department of Neuroscience, School of Medicine, "Federico II" University of Naples, Via Pansini 5, 80131 Naples, Italy. Email: lannunzi{at}unina.it

The superfamily of cation/Ca²⁺ plasma–membrane exchangers contains two branches, the K⁺-independent Na⁺–Ca²⁺ exchangers (NCXs) and the K⁺-dependent Na⁺–Ca²⁺ exchangers (NCKXs), widely expressed in mammals. NCKX2 is the major neuronally expressed isoform among NCKX members. Despite its importance in maintaining Na⁺, Ca²⁺, and K⁺ homeostasis in the CNS, the role of NCKX2 during cerebral ischemia, a condition characterized by an alteration of ionic concentrations, has not yet been investigated. The present study examines NCKX2 role in the development of ischemic brain damage in permanent middle cerebral artery occlusion (pMCAO) and transient middle cerebral artery occlusion. Furthermore, to evaluate the effect of nckx2 ablation on neuronal survival, nckx2–/– primary cortical neurons were subjected to oxygen glucose deprivation plus reoxygenation. NCKX2 mRNA and protein expression was evaluated in the ischemic core and surrounding ipsilesional areas, at different time points after pMCAO in rats. In ischemic core and in periinfarctual area, NCKX2 mRNA and protein expression were downregulated. In addition, NCKX2 knock-down by antisense oligodeoxynucleotide and NCKX2 knock-out by genetic disruption dramatically increased infarct volume. Accordingly, nckx2–/– primary cortical neurons displayed a higher vulnerability and a greater [Ca²⁺]_i increase under hypoxic conditions, compared with nckx2+/+ neurons. In addition, NCKX currents both in the forward and reverse mode of operation were significantly reduced in nckx2–/– neurons compared with nckx2+/+ cells. Overall, these results indicate that NCKX2 is involved in brain ischemia, and it may represent a new potential target to be investigated in the study of the molecular mechanisms involved in cerebral ischemia.

Key words: NCKX; MCAO; cerebral ischemia; sodium–calcium exchanger; antisense strategy; knock-out

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Received July 15, 2007; revised Dec. 24, 2007; accepted Jan. 6, 2008.

Correspondence should be addressed to Dr. Lucio Annunziato, Division of Pharmacology, Department of Neuroscience, School of Medicine, "Federico II" University of Naples, Via Pansini 5, 80131 Naples, Italy. Email: lannunzi{at}unina.it

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