GABRA3

Official Full Name

gamma-aminobutyric acid type A receptor subunit alpha3

Organism

Homo sapiens

GeneID

2556

Background

GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. At least 16 distinct subunits of GABA-A receptors have been identified. [provided by RefSeq, Jul 2008]

Synonyms

EPILX2;

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Detailed Information

Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter. GABA exerts function through two types of GABA receptors: the metabotropic GABAB receptor and the ionotropic receptors including GABAA and GABAC receptors. Gabra3 is a subunit of the GABA type A receptor, which is a chloride channel comprised of various subunits. The dysregulation of GABA type A receptors, such as GABA transporter and GABA transaminase, has been suggested to be involved in the brain metastases of breast cancer. It has been proposed that metastatic breast cancer cells might use GABA in stimulating normal neuronal cells to proliferate.

GABRA3 and cancer

Recent studies demonstrated that the GABRA3 protein promotes metastasis by increasing the expression of matrix metalloproteinases (MMPs) through the AKT pathway in lung and breast cancer. MMPs are secreted proteins which are able to degrade extracellular matrix (ECM) proteins such as collagen, but also proteins involved in cell-cell junctions.

Using bioinformatic analysis of breast cancer genomics data, researchers discovered that high expression of Gabra3 is significantly inversely correlated with breast cancer survival. They show that overexpression of Gabra3 promotes breast cancer cell migration, metastasis and invasion. In contrast, the knockdown of Gabra3 expression suppresses cell invasion and metastasis with no detectable effect on cell proliferation. Importantly, these studies suggest that Gabra3 is highly expressed in breast cancer tissues and cell lines but not in normal breast epithelial cells or normal breast tissue. Mechanistically, it shows that 1) Gabra3 activates the AKT pathway to promote cell migration and invasion; 2) A-to-I editing of Gabra3 occurs only in non-invasive breast cancer cells; 3) RNA-edited Gabra3 transdominantly suppresses the functions of unedited Gabra3 in promoting cell invasion and metastasis.

BT-GABRA3 and CT-GABRA3 transcripts

The GABRA3 gene locus exists of two overlapping transcripts: BT-GABRA3 that is expressed specifically in brain and testis; and CT-GABRA3 that is expressed exclusively in testis. CT-GABRA3 exhibits typical features of a "cancer-germline" genes (CG genes), since it shows promoter hypomethylation and transcriptional activation in many tumors. CT-GABRA3 carries a clustered pair of miRNAs (miR-105 and miR-767), which show concurrent expression in tumors. An independent group identified miR-105 as an important promoter of cancer metastasis, owing to its ability to weaken vascular endothelial barriers following exosomal secretion. On the other hand, miR-767 inhibits expression of TET1, a gene with tumor suppressive functions involved in epigenetic processes of DNA demodification. Moreover, the studies revealed that CT-GABRA3 hypomethylation/activation in tumors is correlated with hypermethylation of the downstream BT-GABRA3 promoter. Finally, it was found that in tumor cells where the BT-GABRA3 promoter is hypermethylated, the gene becomes sensitive to DNA demethylation, indicating a process of epigenetic switch. Together these studies revealed the existence of a novel miRNA-producing CG gene with oncogenic potential.

Figure 1. Proposed mechanism of activation of CT-GABRA3 by hypomethylation creates a methylation-dependent chromatin environment on the downstream BT-GABRA3 promoter.

References:

Liu L, et al. GABRA3promotes lymphatic metastasis in lung adenocarcinoma by mediating upregulation of matrix metalloproteinases. Oncotarget, 2016, 7(22):32341-32350.
Long M, et al. miR-92b-3p acts as a tumor suppressor by targeting Gabra3 in pancreatic cancer. Molecular Cancer, 2017, 16(1):167.
Kiranmai G, et al. The mRNA-edited form of GABRA3 suppresses GABRA3-mediated Akt activation and breast cancer metastasis. Nature Communications, 2016, 7:10715.
Tongelen VA, Identification of a novel cancer-germline transcript within the miRNA harboring GABRA3 gene: epigenetic alterations of the locus in tumors. 2017

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