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Review
. 2016:76:103-45.
doi: 10.1016/bs.apha.2016.01.004. Epub 2016 Mar 24.

Transcriptional Regulation of Glutamate Transporters: From Extracellular Signals to Transcription Factors

Z Martinez-Lozada  1 , A M Guillem  1 , M B Robinson  2
Affiliations
Review

Transcriptional Regulation of Glutamate Transporters: From Extracellular Signals to Transcription Factors

Z Martinez-Lozada et al. Adv Pharmacol. 2016.

Abstract

Glutamate is the predominant excitatory neurotransmitter in the mammalian CNS. It mediates essentially all rapid excitatory signaling. Dysfunction of glutamatergic signaling contributes to developmental, neurologic, and psychiatric diseases. Extracellular glutamate is cleared by a family of five Na(+)-dependent glutamate transporters. Two of these transporters (GLAST and GLT-1) are relatively selectively expressed in astrocytes. Other of these transporters (EAAC1) is expressed by neurons throughout the nervous system. Expression of the last two members of this family (EAAT4 and EAAT5) is almost exclusively restricted to specific populations of neurons in cerebellum and retina, respectively. In this review, we will discuss our current understanding of the mechanisms that control transcriptional regulation of the different members of this family. Over the last two decades, our understanding of the mechanisms that regulate expression of GLT-1 and GLAST has advanced considerably; several specific transcription factors, cis-elements, and epigenetic mechanisms have been identified. For the other members of the family, little or nothing is known about the mechanisms that control their transcription. It is assumed that by defining the mechanisms involved, we will advance our understanding of the events that result in cell-specific expression of these transporters and perhaps begin to define the mechanisms by which neurologic diseases are changing the biology of the cells that express these transporters. This approach might provide a pathway for developing new therapies for a wide range of essentially untreatable and devastating diseases that kill neurons by an excitotoxic mechanism.

Keywords: Astrocytes; EAAC1; EAAT; GLAST; GLT-1; Glu uptake; Transcriptional regulation.

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Conflict of interest statement

Conflict of interest statement

The authors have no conflicts to declare.

Figures

Figure 1
Figure 1. Schematic representation of evolutionary conserved domains in the promoter regions of Glu transporters
The mouse and human homologs of the genes encoding GLAST, GLT-1, EAAC1, EAAT4 or EAAT5 were aligned using an online resources (DCODE database; http://ecrbase.dcode.org). Rectangular boxes represent evolutionary conserved domains, defined as regions of ≥70% homology for at least 100 nucleotides. It is important to remember that enhancer elements can be outside the regions aligned and that some of the distal conserved regions may not be involved in transport regulation and may instead, regulate the neighboring gene.
Figure 2
Figure 2. Schematic representation of the signaling pathways that regulate transcription of GLAST/EAAT1/SLC1A3
Several signaling pathways activated in response to extracellular molecules regulate the expression of GLAST by activating transcription factors that interact with cis elements in the promoter. The pathways that increase or decrease GLAST transcription are depicted in different schematics (Panel A & B, respectively). For a detailed description see the text. TX: Tamoxifen, E2: Estrogen, Glu: Glu, AC: adenylate cyclase, ET1: endothelin-1, ETA, ETB: Endothelin receptors A and B.
Figure 2
Figure 2. Schematic representation of the signaling pathways that regulate transcription of GLAST/EAAT1/SLC1A3
Several signaling pathways activated in response to extracellular molecules regulate the expression of GLAST by activating transcription factors that interact with cis elements in the promoter. The pathways that increase or decrease GLAST transcription are depicted in different schematics (Panel A & B, respectively). For a detailed description see the text. TX: Tamoxifen, E2: Estrogen, Glu: Glu, AC: adenylate cyclase, ET1: endothelin-1, ETA, ETB: Endothelin receptors A and B.
Figure 3
Figure 3. Schematic representation of the signaling pathways that regulate transcription of GLT-1/EAAT2/SLC1A2
Several signaling pathways activated in response to extracellular molecules regulate the expression of GLT-1 by activating transcription factors that interact with cis elements in the promoter. The pathways that increase or decrease GLT-1 transcription are depicted in different schematics (Panel A & B, respectively). For a detail description see the text. TX: tamoxifen, E2: estrogen, AC: adenylate cyclase, GR: glucocorticoid receptor, MR: mineralocorticoid receptor.
Figure 3
Figure 3. Schematic representation of the signaling pathways that regulate transcription of GLT-1/EAAT2/SLC1A2
Several signaling pathways activated in response to extracellular molecules regulate the expression of GLT-1 by activating transcription factors that interact with cis elements in the promoter. The pathways that increase or decrease GLT-1 transcription are depicted in different schematics (Panel A & B, respectively). For a detail description see the text. TX: tamoxifen, E2: estrogen, AC: adenylate cyclase, GR: glucocorticoid receptor, MR: mineralocorticoid receptor.
Figure 4
Figure 4. Schematic representation of the signaling pathways that regulate transcription of EAAC1/EAAT3/SLC1A1
Extracellular signals and transcription factors that have been associated with an increase in EAAC1 expression are shown. For a detail description see the text. ACM: astrocyte conditioned media, ROS: reactive oxygen species.
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