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The Journal of Neuroscience, November 23, 2005, 25(47):10822-10830; doi:10.1523/JNEUROSCI.3912-05.2005

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Cellular/Molecular
Downstream Regulatory Element Antagonist Modulator Regulates Ca²⁺ Homeostasis and Viability in Cerebellar Neurons

Rosa Gomez-Villafuertes,^1 * Begoña Torres,^1 * Jorge Barrio,^1 * Magali Savignac,¹ Nadia Gabellini,² Federico Rizzato,² Belen Pintado,³ Alfonso Gutierrez-Adan,³ Britt Mellström,¹ Ernesto Carafoli,^2,4 and Jose R. Naranjo¹

¹Department of Molecular and Cellular Biology, National Centre of Biotechnology, Consejo Superior de Investigaciones Científicas, E-28049 Madrid, Spain, ²Department of Biological Chemistry, University of Padova, I-35121 Padova, Italy, ³Department of Animal Reproduction, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, E-28040 Madrid, Spain, and ⁴Venetian Institute of Molecular Medicine, I-35121 Padova, Italy

The Na⁺/Ca²⁺ exchangers NCX1, NCX2, and NCX3 are vital for the control of cellular Ca²⁺ homeostasis. Here, we show that a doublet of downstream regulatory element sites in the promoter of the NCX3 gene mediates transcriptional repression of NCX3 by the Ca²⁺-modulated transcriptional repressor downstream regulatory element antagonist modulator (DREAM). Overexpression of a DREAM EF-hand mutant insensitive to Ca²⁺ (EFmDREAM) in hippocampus and cerebellum of transgenic mice significantly reduced NCX3 mRNA and protein levels without modifying NCX1 and NCX2 expression. Cerebellar granules from EFmDREAM transgenic mice showed increased levels of cytosolic Ca²⁺ and were more vulnerable to increased Ca²⁺ influx after partial opening of voltage-gated plasma membrane Ca²⁺ channels induced by increasing K⁺ in the culture medium but survived better in the conditions of reduced Ca²⁺ influx prevailing in low extracellular K⁺. Overexpression of NCX3 in EFmDREAM transgenic granules using a lentiviral vector restored the normal survival response to high K⁺ observed in wild-type granules. Thus, the downregulation of the regulator of Ca²⁺ homeostasis NCX3 by Ca²⁺-regulated DREAM is a striking example of the autoregulatory property of the Ca²⁺ signal in neurons.

Key words: calcium; gene expression; cerebellar granules; EF hands; lentivirus; Na⁺/Ca²⁺ exchangers

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Received July 29, 2005; accepted October 4, 2005.

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