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.
Pubmed ID: 25597433 RIS Download
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The TFSEARCH searches highly correlated sequence fragments against TFMATRIX transcription factor binding site profile database in the "TRANSFAC" databases developed at GBF-Braunschweig, Germany. The TFSEARCH program was written by Yutaka Akiyama (Kyoto University, currently at RWCP) in 1995.
View all literature mentionsAn integrated web tool for transcription factor binding site search and visualization. Both the Python Scripts for Offline Scanning and the Python implementation of the LASAGNA algorithm are available.
View all literature mentionsSoftware used for Bio-Rad imaging systems to acquire, quantitate, and analyze a variety of data. The software allows automatic configuration of imaging systems with appropriate filters, lasers, LEDs, and other illumination sources. It also contains tools for automated analysis of tests and assays such as 1-D electrophoretic gels, western blots, and colony counts.
View all literature mentionsCell line SH-SY5Y is a Cancer cell line with a species of origin Homo sapiens (Human)
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