The mitochondrial aspartate/glutamate carrier isoform 1 gene expression is regulated by CREB in neuronal cells. (March 2015)

• Record Type: Journal Article
• Authors: Menga, Alessio; Iacobazzi, Vito; Infantino, Vittoria; Avantaggiati, Maria Laura; Palmieri, Ferdinando
• Is Part Of: International journal of biochemistry & cell biology. Volume 60(2015:Mar.)
• Page Start: 157
• Page End: 166
• Publication Date: 2015-03
• Subjects: Aβ β-amyloid -- AGC1 aspartate/glutamate carrier isoform 1 -- APP amyloid precursor protein -- BAPTA-AM 1, 2-bis(2-aminophenoxy) ethane-N, N, N′, N′-tetraacetic acid tetrakis(acetoxymethyl ester) -- ChIP chromatin immunoprecipitation -- P-CREB phospho-cAMP-response-element-binding protein -- T-CREB total-cAMP-response-element-binding protein db-cAMP, dibutyryl-cAMP -- EMSA electrophoreticmobility-shift assay -- IBMX isobutylmethylxanthine -- IFNγ interferon gamma -- LUC luciferase -- NAA N-acetylaspartate -- NRG-1 neuregulin-1 -- PKA cAMP-dependent protein kinase -- SAP97 synapse-associated protein-97 -- siCREB siRNA targeting CREB -- siRNA small interfering RNA -- SYP synaptophysin -- TNFα tumor necrosis factor alpha -- WB Western-blotting; Aspartate/glutamate carrier -- CREB -- Ca2+; Biochemistry -- Periodicals; Cytology -- Periodicals; Biochemistry -- Periodicals; Cell Biology -- Periodicals; Biochimie -- Périodiques; Cytologie -- Périodiques; Biochimie; Cytologie; Biochemistry; Cytology; Ressource Internet (Descripteur de forme); Périodique électronique (Descripteur de forme); Periodicals; 572.05
• DOI: 10.1016/j.biocel.2015.01.004
• Languages: English
• ISSNs: 1357-2725

Abstract

Highlights: SLC25A12 gene expression is regulated in SH-SY5Y cells through CREB. SLC25A12 gene is up-regulated in SH-SY5Y cells under conditions of differentiation. Ca 2+ interaction with CREB further enhances SLC25A12 gene expression. SLC25A12 gene is down-regulated in neuroinflammation. SLC25A12 gene is up-regulated in SH-SY5Y cells by neuregulin-1. 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.