GABRD
   HOME

TheInfoList



OR:

Gamma-aminobutyric acid receptor subunit delta is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''GABRD''
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. In the mammalian brain, the delta (δ) subunit forms specific GABAA receptor subtypes by co-assembly leading to δ subunit containing GABAA receptors (δ-GABAA receptors).


Structure and function

The delta (δ) subunit, one of the subunits of the hetero-pentameric δ-GABAA receptors, is a determinant subunit for the specific cellular localization of δ-GABAA receptors, which are modulated by the GABA. GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts on the repertoire of GABAA 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 GABAA receptors associated with extrasynaptic activity, mediating tonic inhibition, which is slower compared to classica
inhibition
(phasic or synaptic inhibition). The most common GABAA receptors have the gamma subunit, which allows the receptor to bind
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
s. For this reason, receptors containing δ-subunits (δ-GABAA receptor) are sometimes referred to as “benzodiazepine-insensitive” GABAA 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 The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is the ...
(VTA) pathway in the brain's
hippocampus The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...
, which means that they may have implications in learning, memory, and reward.


Cloning of GABAA receptor

GABAA 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 A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
: α1-α6, β1-β3, γ1-γ3 subunits and one δ subunit.


Cell type-specific expression

The cellular localization of mRNAs of 13 GABAA receptor subunits was analyzed in different brain regions. For example, in the
cerebellum The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebel ...
, various receptor subtypes are found in
cerebellar granule cell Cerebellar granule cells form the thick granular layer of the cerebellar cortex and are among the smallest neurons in the brain. (The term granule cell is used for several unrelated types of small neurons in various parts of the brain.) Cereb ...
s and
Purkinje cell Purkinje cells, or Purkinje neurons, are a class of GABAergic inhibitory neurons located in the cerebellum. They are named after their discoverer, Czech people, Czech anatomist Jan Evangelista Purkyně, who characterized the cells in 1839. Stru ...
s, whereas in the
olfactory bulb The olfactory bulb (Latin: ''bulbus olfactorius'') is a grey matter, neural structure of the vertebrate forebrain involved in olfaction, the sense of odor, smell. It sends olfactory information to be further processed in the amygdala, the orbitof ...
,
periglomerular cell Periglomerular cells mediate lateral inhibition in the olfactory system together with granule cells. They have inhibitory synapses on mitral cells and tufted cell Tufted cells are found within the olfactory glomeruli. They receive input from the ...
s,
tufted cell Tufted cells are found within the olfactory glomeruli. They receive input from the receptor cells of the olfactory epithelium found in areas of the nose able to sense smell. Both tufted cells and mitral cells are called projection neurons. Projecti ...
s, and internal granule cells express GABAA 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 Digital polymerase chain reaction (digital PCR, DigitalPCR, dPCR, or dePCR) is a biotechnology, biotechnological refinement of conventional polymerase chain reaction methods that can be used to directly quantify and clonally amplify nucleic acids ...
, the expression of the rat ''gabrd'' gene was examined across three cell types in the
somatosensory cortex In physiology, the somatosensory system is the network of neural structures in the brain and body that produce the perception of touch (haptic perception), as well as temperature (thermoception), body position (proprioception), and pain. It is ...
: neurogliaform cells, fast spiking
basket cell Basket cells are inhibitory GABAergic interneurons of the brain, found throughout different regions of the cortex and cerebellum. Anatomy and physiology Basket cells are multipolar GABAergic interneurons that function to make inhibitory synapses ...
s and
pyramidal cell Pyramidal cells, or pyramidal neurons, are a type of multipolar neuron found in areas of the brain including the cerebral cortex, the hippocampus, and the amygdala. Pyramidal neurons are the primary excitation units of the mammalian prefrontal cor ...
s. 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 Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an Alcohol (chemistry), alcohol with the chemical formula . Its formula can be also written as or (an ethyl ...
, and appears to contribute strongly to pathological
alcohol dependence Alcohol dependence is a previous (DSM-IV and ICD-10) psychiatric diagnosis in which an individual is physically or psychologically dependent upon alcohol (also chemically known as ethanol). In 2013, it was reclassified as alcohol use disorde ...
.


δ-subunit GFP tagging

Subunits of GABA A receptors were tagged by
Green Fluorescent Protein The green fluorescent protein (GFP) is a protein that exhibits bright green fluorescence when exposed to light in the blue to ultraviolet range. The label ''GFP'' traditionally refers to the protein first isolated from the jellyfish ''Aequorea ...
(GFP) or its variants (EGFP) to study
trafficking Smuggling is the illegal transportation of objects, substances, information or people, such as out of a house or buildings, into a prison, or across an international border, in violation of applicable laws or other regulations. There are various ...
, localization,
oligomerization In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relative ...
, and protein interactions of relevant receptor subtypes and the relevant subunits. Typically, the EGFP or GFP tagging has been done in the
N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
or
C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
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 The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
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

* GABAA receptor


References


Further reading

* * *


External links

* {{Ligand-gated ion channels Ion channels