GAD2

Official Full Name

glutamate decarboxylase 2

Organism

Homo sapiens

GeneID

2572

Background

This gene encodes one of several forms of glutamic acid decarboxylase, identified as a major autoantigen in insulin-dependent diabetes. The enzyme encoded is responsible for catalyzing the production of gamma-aminobutyric acid from L-glutamic acid. A pathogenic role for this enzyme has been identified in the human pancreas since it has been identified as an autoantibody and an autoreactive T cell target in insulin-dependent diabetes. This gene may also play a role in the stiff man syndrome. Alternative splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Oct 2008]

Synonyms

GAD65;

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Detailed Information

γ-Aminobutyric acid (GABA), the main inhibitory neurotransmitter in mammalian brain, has been implicated in brain development and schizophrenia. The glutamate decarboxylase 1 and 2 (GAD1 and GAD2) control GABA synthesis, but only the former has been clearly implicated in schizophrenia. GAD1 and GAD2 are located on different chromosomes in mammals and encode two major isoforms of the GAD enzyme, GAD67 and GAD65 respectively. Within cells, GAD2 full length protein (65kDa) is maintained in a largely inactive form, apoGAD, (about 93%), which is converted to an enzymatically active form by the binding of pyridoxal 5’-phosphate. Studies of GAD2 in postmortem brains of patients with schizophrenia have been inconsistent and mostly negative. In prefrontal cortex (PFC), GAD2 expression has been reported as decreased, normal and increased in patients with schizophrenia.

Epigenetic regulation of Gad2 transcription

In a recent study on central pain-modulating neurons in the brainstem, it was reported that persistent pain conditions epigenetically decreased Gad2 transcription in chronic pain animal models. Through ChIP assays, the suppressed Gad2 transcription was found to result from decreased histone H3 acetylation in the regions of -646/-484 and -285/-153 bp upstream of TSS in the Gad2 gene. This is in general agreement with prior reports of multiple Gad2 promoter regions identified from a reporter gene system in vitro. Currently, it has not to be determined what transcription factors or gene repressors are involved in the pain-induced H3 hypoacetylation at Gad2. Given the previous reports of CREB regulation of Gad2 transcription and the presence of CRE in the DNA regions of pain activity-regulated chromatin remodeling, it is probable that these pain-related regulatory regions contain or overlap with DNA elements that function as CREB-mediated enhancers to control Gad2 transcription (Figure 1).

Figure 1. Transcriptional control of Gad2.

Gad2 and neurological diseases

Given the activity-dependent GAD65 function and particularly, activity-regulated Gad2 expression by epigenetic control of transcription, Gad2 could play a more important role in the chronic disease condition-induced plasticity of central GABA synapses. Suppression of Gad2 transcriptional expression and resultant impairment in GABA synaptic release and inhibitory GABA function might contribute significantly to the development of these disease conditions.

In fact, the evidence is accumulating in support of the Gad2 role. For instance, GAD65 expression is significantly downregulated in subjects with bipolar disorder or schizophrenia and in the hippocampus of a mouse model of chronic depression. Gad2 KO mice display sensitized pain behaviors through histone hypoacetylation-induced downregulation of Gad2. Viral delivery of the Gad2 gene or histone hyperacetylation-induced upregulation of Gad2 inhibits pain. Interestingly, drugs that increase histone acetylation have been used to treat epilepsy, anxiety, depression and bipolar disorders. Thus, Gad2 and its transcriptional control could serve as a novel therapeutic target to restore the impaired GABA inhibitory function involved in these neurological diseases.

References:

Veerasakul S, et al. Association of polymorphisms in GAD1 and GAD2 genes with methamphetamine dependence. Pharmacogenomics, 2017, 18(1):17.
Davis K N, et al. GAD2 Alternative Transcripts in the Human Prefrontal Cortex, and in Schizophrenia and Affective Disorders. Plos One, 2016, 11(2):e0148558.
Blednov Y A, et al. Mice lacking Gad2 show altered behavioral effects of ethanol, flurazepam and gabaxadol. Addiction Biology, 2010, 15(1):45-61.
Pan Z Z. Transcriptional control of Gad2. Transcription, 2012, 3(2):68-72.

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