GABRD

Gamma-aminobutyric acid receptor subunit delta is a protein that in humans is encoded by the ''GABRD'' gene. In the mammalian brain, the delta (δ) subunit forms specific GABA_A receptor subtypes by co-assembly leading to δ subunit containing GABA_A receptors (δ-GABA_A receptors).

Structure and function

The delta (δ) subunit, one of the subunits of the hetero-pentameric δ-GABA_A receptors, is a determinant subunit for the specific cellular localization of δ-GABA_A receptors, which are modulated by the GABA. GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts on the repertoire of GABA_A receptors, the ligand-gated chloride channels. It is assembled from a diverse subunit pool, including assemblies from a family of 19 subunits (α1-α6, β1-β3, γ1-γ3, δ, ∈, θ, π and ρ1-ρ3). The GABRD gene encodes the delta (δ) subunit. Specifically, the δ-subunit is usually expressed in GABA_A receptors associated with extrasynaptic activity, mediating tonic inhibition, which is slower compared to classica
inhibition
(phasic or synaptic inhibition). The most common GABA_A receptors have the gamma subunit, which allows the receptor to bind benzodiazepines. For this reason, receptors containing δ-subunits (δ-GABA_A receptor) are sometimes referred to as “benzodiazepine-insensitive” GABA_A receptors. However, they do show an exquisitely high sensitivity to ethanol compared to the benzodiazepine-sensitive receptors, which do not respond to ethanol however these results are not fully confirmed in the literature. The δ-subunit containing receptors are also known to be involved in the ventral tegmental area (VTA) pathway in the brain's hippocampus, which means that they may have implications in learning, memory, and reward.

Cloning of GABA_A receptor

GABA_A receptors were initially cloned by the classical method that the peptide sequences obtained from purified (bovine brain) receptors were used to construct synthetic DNA probes to screen brain cDNA libraries. Eventually, this technique have led to the identification of most of the gene family with its isoforms: α1-α6, β1-β3, γ1-γ3 subunits and one δ subunit.

Cell type-specific expression

The cellular localization of mRNAs of 13 GABA_A receptor subunits was analyzed in different brain regions. For example, in the cerebellum, various receptor subtypes are found in cerebellar granule cells and Purkinje cells, whereas in the olfactory bulb, periglomerular cells, tufted cells, and internal granule cells express GABA_A receptor subtypes. Specifically, the pattern of cell type-specific δ subunit expression is shown in the table below.

In a technical comparison between quantitative reverse transcriptase PCR and digital PCR, the expression of the rat ''gabrd'' gene was examined across three cell types in the somatosensory cortex: neurogliaform cells, fast spiking basket cells and pyramidal cells. Gene expression was detected in all three cell types, but showed marked enrichment in neurogliaform cells versus the other cell types examined. The GABAA receptor delta subunit is profoundly downregulated with chronic intermittent exposure to ethanol, and appears to contribute strongly to pathological alcohol dependence.

δ-subunit GFP tagging

Subunits of GABA _A receptors were tagged by Green Fluorescent Protein (GFP) or its variants (EGFP) to study trafficking, localization, oligomerization, and protein interactions of relevant receptor subtypes and the relevant subunits. Typically, the EGFP or GFP tagging has been done in the N-terminus or C-terminus of the mature peptide sequence of relevant subunit. The GFP tagging of δ-subunit was performed in the different domains of the subunit such as the N-terminus, C-terminus as well as intracellular (cytoplasmic) domain. Nevertheless, despite these and other studies, it is not clear if this subunit requires α and β subunits for the membrane targeting since literature suggests conflicting results. By the use of GFP tagging of this subunit, one group reported that the cell membrane expression of the δ subunit was observed only in the presence of both α and β subunits. However, another group suggested that the δ subunit can target to the cell membrane and the βδ containing receptors exist.

See also

* GABA_A receptor

References

Further reading

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External links

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{{Ligand-gated ion channels

Ion channels