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NCX1 Exchanger Cooperates with Calretinin to Confer Preconditioning-Induced Tolerance Against Cerebral Ischemia in the Striatum

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Abstract

Recently, the Na+/Ca+2 exchanger NCX1 and the calcium binding protein calretinin have emerged as new molecular effectors of delayed preconditioning in the brain. In the present study, we investigated whether NCX1 and calretinin cooperate within the preconditioned striatum to confer neurons greater resistance to degeneration. Confocal microscopy analysis revealed that NCX1 expression was upregulated in calretinin-positive interneurons in the rat striatum after tolerance induction. Consistently, coimmunoprecipitation assays performed on human SHSY-5Y cells, a neuronal cell line which constitutively expresses calretinin, revealed a binding between NCX1 and calretinin. Finally, silencing of calretinin expression, both in vitro and in vivo, significantly prevented preconditioning-induced neuroprotection. Interestingly, our biochemical and functional studies showed that the selective silencing of calretinin in brain cells significantly prevented not only the preconditioning-induced upregulation of NCX1 expression and activity but also the activation of the prosurvival protein kinase Akt, which is involved in calretinin and NCX1 protective actions. Collectively, our results indicate that the Na+/Ca+2 exchanger NCX1 and the calcium binding protein calretinin cooperate within the striatum to confer tolerance against cerebral ischemia.

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Acknowledgments

This work was supported by grants PON01_01602 by MIUR and PON03PE_00146_1 by MIUR to LA, from Fondazione Italiana Sclerosi Multipla FISM 2012/R/1 to F.B, and Ricerca Sanitaria Progetto GR-2010-2318138 from Ministero della Salute to A. S. We thank Dr. Paola Merolla for the editorial revision and Mr. Carmine Capitale for technical support.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, Federico II University of Naples, Naples, Italy

    Francesca Boscia, Antonella Casamassa, Agnese Secondo, Alba Esposito, Anna Pannaccione, Giuseppe Pignataro, Ornella Cuomo, Antonio Vinciguerra, Valeria de Rosa & Lucio Annunziato

  2. Fondazione IRCSS SDN, Naples, Italy

    Rossana Sirabella & Lucio Annunziato

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  1. Francesca Boscia
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Correspondence to Lucio Annunziato.

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Boscia, F., Casamassa, A., Secondo, A. et al. NCX1 Exchanger Cooperates with Calretinin to Confer Preconditioning-Induced Tolerance Against Cerebral Ischemia in the Striatum. Mol Neurobiol 53, 1365–1376 (2016). https://doi.org/10.1007/s12035-015-9095-4

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