title: The mitochondrial aspartate/glutamate carrier isoform 1 gene expression is regulated by CREB in neuronal cells.
abstract: The aspartate/glutamate carrier isoform 1 is an essential mitochondrial transporter that exchanges intramitochondrial aspartate and cytosolic glutamate across the inner mitochondrial membrane. It is expressed in brain, heart and muscle and is involved in important biological processes, including myelination. However, the signals that regulate the expression of this transporter are still largely unknown. In this study we first identify a CREB binding site within the aspartate/glutamate carrier gene promoter that acts as a strong enhancer element in neuronal SH-SY5Y cells. This element is regulated by active, phosphorylated CREB protein and by signal pathways that modify the activity of CREB itself and, most noticeably, by intracellular Ca(2+) levels. Specifically, aspartate/glutamate carrier gene expression is induced via CREB by forskolin while it is inhibited by the PKA inhibitor, H89. Furthermore, the CREB-induced activation of gene expression is increased by thapsigargin, which enhances cytosolic Ca(2+), while it is inhibited by BAPTA-AM that reduces cytosolic Ca(2+) or by STO-609, which inhibits CaMK-IV phosphorylation. We further show that CREB-dependent regulation of aspartate/glutamate carrier gene expression occurs in neuronal cells in response to pathological (inflammation) and physiological (differentiation) conditions. Since this carrier is necessary for neuronal functions and is involved in myelinogenesis, our results highlight that targeting of CREB activity and Ca(2+) might be therapeutically exploited to increase aspartate/glutamate carrier gene expression in neurodegenerative diseases.
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Via Orabona 4, 70125 Bari, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Menga
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Via Orabona 4, 70125 Bari, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Iacobazzi
authors.affiliation: Department of Science, University of Basilicata, Via N. Sauro 85, 85100 Potenza, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Infantino
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Avantaggiati
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Via Orabona 4, 70125 Bari, Italy. Electronic address: ferdpalmieri@gmail.com.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Palmieri
mesh_terms: D053674:Aggrecans / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D020890:Neuregulin-1 / Q000494:pharmacology; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: C508319:ACAN protein, human; D053674:Aggrecans; D017362:Cyclic AMP Response Element-Binding Protein; D033681:Mitochondrial Membrane Transport Proteins; D020890:Neuregulin-1; C114606:SLC25A12 protein, human; D002118:Calcium
keywords: Aspartate/glutamate carrier; CREB; Ca(2+)