GABRD

GABRD
Identifiers
Aliases	GABRD, EIG10, EJM7, GEFSP5, gamma-aminobutyric acid type A receptor delta subunit, gamma-aminobutyric acid type A receptor subunit delta
External IDs	OMIM: 137163; MGI: 95622; HomoloGene: 55489; GeneCards: GABRD; OMA:GABRD - orthologs
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1p36.33 Start 2,019,329 bp[1] End 2,030,758 bp[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4|4 E2 Start 155,469,437 bp[2] End 155,482,569 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right hemisphere of cerebellum right frontal lobe cerebellar vermis paraflocculus of cerebellum prefrontal cortex primary visual cortex dorsolateral prefrontal cortex Brodmann area 9 cingulate gyrus anterior cingulate cortex Top expressed in cerebellar cortex lobe of cerebellum cerebellar vermis superior frontal gyrus dorsal striatum lateral geniculate nucleus olfactory tubercle primary visual cortex nucleus accumbens medial dorsal nucleus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding chloride channel activity extracellular ligand-gated ion channel activity GABA-A receptor activity ion channel activity transmembrane signaling receptor activity transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential Cellular component chloride channel complex integral component of membrane cell junction GABA-A receptor complex postsynaptic membrane plasma membrane synapse integral component of plasma membrane membrane glutamatergic synapse GABA-ergic synapse integral component of postsynaptic membrane neuron projection Biological process ion transmembrane transport chloride transport chloride transmembrane transport ion transport chemical synaptic transmission signal transduction regulation of membrane potential nervous system process regulation of postsynaptic membrane potential Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2563 14403 Ensembl ENSG00000187730 ENSMUSG00000029054 UniProt O14764 P22933 RefSeq (mRNA) NM_000815 NM_008072 RefSeq (protein) NP_000806 NP_032098 Location (UCSC) Chr 1: 2.02 – 2.03 Mb Chr 4: 155.47 – 155.48 Mb PubMed search [3] [4]
Wikidata
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Gamma-aminobutyric acid receptor subunit delta is a protein that in humans is encoded by the GABRD gene.^[5][6][7] 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).^[8]

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,^[8][9] 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).^[10][9] The GABRD gene encodes the delta (δ) subunit.^[7] Specifically, the δ-subunit is usually expressed in GABA_A receptors associated with extrasynaptic activity, mediating tonic inhibition, which is slower compared to classical inhibition (phasic or synaptic inhibition).^[9] 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.^[8] 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.^[11]

Clinical significance

Neurological and psychiatric disorders

Mutations or dysregulation of GABRD and other GABA-A receptor subunits have been implicated in conditions such as epilepsy, anxiety disorders, and certain neurodevelopmental disorders.^[12][13]

Research has suggested that alterations in the GABRD gene may be linked to certain neurological and psychiatric disorders, including anxiety. Anxiety disorders are a group of mental health conditions characterized by excessive and persistent worry, fear, or nervousness. The GABA system, including the GABRD gene, is implicated in the regulation of anxiety and stress responses. While there is ongoing research to understand the complex genetic and neurobiological factors contributing to anxiety disorders, it's important to note that anxiety is a multifaceted condition influenced by a combination of genetic, environmental, and psychological factors. Many genes, neurotransmitters, and brain regions are likely involved in the development and manifestation of anxiety. Individuals with variations in the GABRD gene may exhibit differences in GABA-A receptor function, which could potentially influence their susceptibility to anxiety or other related conditions. However, the interplay of genetics with environmental factors is complex, and it's crucial to consider a holistic perspective when understanding the causes of anxiety.^[14]

Epilepsy is a neurological disorder characterized by recurrent, unprovoked seizures. GABAergic neurotransmission, mediated by the GABA-A receptor, is essential for maintaining the balance between excitatory and inhibitory signals in the brain. Changes in the functioning of GABA receptors, including those associated with the GABRD gene, can influence this balance and potentially contribute to the development of epilepsy. Research has suggested that alterations in the GABRD gene may be implicated in certain forms of epilepsy. Mutations or variations in genes encoding GABA receptor subunits can affect the function of these receptors, leading to an imbalance in excitatory and inhibitory neurotransmission, which may contribute to the hyperexcitability observed in epilepsy. It's important to note that epilepsy is a complex disorder with various genetic and environmental factors contributing to its development. While some individuals with epilepsy may have genetic mutations affecting GABA receptors, not all cases are directly linked to specific genes.^[15]

GABA levels, known as the neurotransmitter, one of the most important signals of the mammalian brain, have recently been involved in mood disorders. Genetic studies have also shown that some genes are involved in mood disorders. GABARD is one of the strong candidates among these genes. As a result of studies, it has been proven that the 8 subunits encoded by GABRD are linked to major depressive disorders.^[16]

Cancer

GABRD effect has also been observed in some types of cancer. For example, GABRD effect has been observed in colorectal cancer. According to research conducted by scientists, it has been observed that colorectal cancers metastasize.^[17] In some neurological diseases, some mutations occur depending on GABRD gene expression, and as a result of these mutations, some diseases occur, for example, epilepsy. Epilepsy is called the sudden discharge process that occurs in the brain, and as a result, sudden contractions occur in the body. but the role of GABRD in epilepsy is less. It has also been observed that it has an effect on autism spectrum disorder as a result of the variation of the GABRD protein.^[18] The GABRD gene encodes the δ subunit of the GABA A receptor, which is highly expressed in the brain and mediates tonic inhibition-related signaling. It has also been proven that excessive release of neurotransmitters plays a role in triggering some types of cancer and uncontrolled cell proliferation. In recent studies, GABRD gene expression is at very high levels in colon adenocarcinoma. In addition, scientists have proven in their research that Gabrd expression is excessive in the relevant tissues.^[19]

Tissue distribution

The cellular localization of mRNAs of 13 GABA_A receptor subunits was analyzed in different brain regions.^[20] 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.^[21] Specifically, the pattern of cell type-specific δ subunit expression is shown in the table below.

Cell type-specific expression of δ subunit and its co-assembly^[8]

Subunit composition	Cell type
α6bδ	Cerebellar granule cells
α1bδ	Hippocampal interneurons, Neocortical interneurons
α4β2δ	Thalamic relay neurons, Striatal spiny neurons, Hippocampal dentate granule cells, Neocortical pyramidal cells

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.^[22] Gene expression was detected in all three cell types, but showed marked enrichment in neurogliaform cells versus the other cell types examined.^[22] The GABAA receptor delta subunit is profoundly downregulated with chronic intermittent exposure to ethanol, and appears to contribute strongly to pathological alcohol dependence.^[23]

The GABRD gene, encoding the delta subunit of the GABAA receptor, exhibits cell type-specific expression patterns. Primarily found in neurons, particularly in brain regions like the hippocampus and cerebral cortex, GABRD plays a crucial role in inhibitory neurotransmission. Its expression dynamically changes during development, influencing synaptic maturation. Emerging evidence suggests GABRD expression in certain glial cells, indicating potential roles in glia-neuron communication. Additionally, GABRD is detected in peripheral tissues, hinting at non-neuronal functions. Altered GABRD expression is linked to neurological disorders, emphasizing its significance.^[24]

Cloning

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.^[9][25][26] 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.^[27]

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.^[28][29][30] 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.^[30] However, another group suggested that the δ subunit can target to the cell membrane and the βδ containing receptors exist.^[31]

See also

• GABA_A receptor

References

1. GRCh38: Ensembl release 89: ENSG00000187730 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000029054 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Sommer B, Poustka A, Spurr NK, Seeburg PH (October 1990). "The murine GABAA receptor delta-subunit gene: structure and assignment to human chromosome 1". DNA and Cell Biology. 9 (8): 561–568. doi:10.1089/dna.1990.9.561. PMID 2176788.
6. Emberger W, Windpassinger C, Petek E, Kroisel PM, Wagner K (Sep 2000). "Assignment of the human GABAA receptor delta-subunit gene (GABRD) to chromosome band 1p36.3 distal to marker NIB1364 by radiation hybrid mapping". Cytogenetics and Cell Genetics. 89 (3–4): 281–282. doi:10.1159/000015636 (inactive 2024-07-16). PMID 10965146. S2CID 83974022.
7. "Entrez Gene: GABRD gamma-aminobutyric acid (GABA) A receptor, delta".
8. Arslan A (March 2021). "Extrasynaptic δ-subunit containing GABA_A receptors". Journal of Integrative Neuroscience. 20 (1): 173–184. doi:10.31083/j.jin.2021.01.284. PMID 33834705. S2CID 233193240.
9. Goetz T, Arslan A, Wisden W, Wulff P (2007). "GABAA receptors: Structure and function in the basal ganglia". GABA(A) receptors: structure and function in the basal ganglia. Progress in Brain Research. Vol. 160. Elsevier. pp. 21–41. doi:10.1016/s0079-6123(06)60003-4. ISBN 978-0-444-52184-2. PMC 2648504. PMID 17499107.
10. Korpi ER, Gründer G, Lüddens H (June 2002). "Drug interactions at GABA(A) receptors". Progress in Neurobiology. 67 (2): 113–159. doi:10.1016/S0301-0082(02)00013-8. PMID 12126658. S2CID 140204981.
11. Vashchinkina E, Panhelainen A, Aitta-Aho T, Korpi ER (2014-11-25). "GABAA receptor drugs and neuronal plasticity in reward and aversion: focus on the ventral tegmental area". Frontiers in Pharmacology. 5: 256. doi:10.3389/fphar.2014.00256. PMC 4243505. PMID 25505414.
12. Dibbens LM, Feng HJ, Richards MC, Harkin LA, Hodgson BL, Scott D, et al. (July 2004). "GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies". Human Molecular Genetics. 13 (13): 1315–1319. doi:10.1093/hmg/ddh146. PMID 15115768.
13. Hong Q, Xu W, Lin Z, Liu J, Chen W, Zhu H, et al. (2020). "Role of GABRD Gene Methylation in the Nucleus Accumbens in Heroin-Seeking Behavior in Rats". Frontiers in Pharmacology. 11: 612200. doi:10.3389/fphar.2020.612200. PMC 7859445. PMID 33551813.
14. Lee V, Sarkar J, Maguire J (March 2014). "Loss of Gabrd in CRH neurons blunts the corticosterone response to stress and diminishes stress-related behaviors". Psychoneuroendocrinology. 41: 75–88. doi:10.1016/j.psyneuen.2013.12.011. PMC 3947777. PMID 24495609.
15. Bhat MA, Guru SA, Mir R, Waza AA, Zuberi M, Sumi MP, et al. (June 2018). "Association of GABAA Receptor Gene with Epilepsy Syndromes". Journal of Molecular Neuroscience. 65 (2): 141–153. doi:10.1007/s12031-018-1081-7. PMID 29785705. S2CID 29167453.
16. Feng Y, Kapornai K, Kiss E, Tamás Z, Mayer L, Baji I, et al. (August 2010). "Association of the GABRD gene and childhood-onset mood disorders". Genes, Brain and Behavior. 9 (6): 668–672. doi:10.1111/j.1601-183X.2010.00598.x. PMC 2935687. PMID 20561060.
17. Niu G, Deng L, Zhang X, Hu Z, Han S, Xu K, et al. (2020). "GABRD promotes progression and predicts poor prognosis in colorectal cancer". Open Medicine. 15 (1): 1172–1183. doi:10.1515/med-2020-0128. PMC 7718617. PMID 33336074.
18. Ahring PK, Liao VW, Gardella E, Johannesen KM, Krey I, Selmer KK, et al. (May 2022). "Gain-of-function variants in GABRD reveal a novel pathway for neurodevelopmental disorders and epilepsy". Brain. 145 (4): 1299–1309. doi:10.1093/brain/awab391. PMC 9630717. PMID 34633442.
19. Wu M, Kim KY, Park WC, Ryu HS, Choi SC, Kim MS, et al. (December 2020). "Enhanced expression of GABRD predicts poor prognosis in patients with colon adenocarcinoma". Translational Oncology. 13 (12): 100861. doi:10.1016/j.tranon.2020.100861. PMC 7484591. PMID 32891902.
20. Wisden W, Laurie DJ, Monyer H, Seeburg PH (March 1992). "The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon". The Journal of Neuroscience. 12 (3): 1040–1062. doi:10.1523/JNEUROSCI.12-03-01040.1992. PMC 6576059. PMID 1312131.
21. Laurie DJ, Seeburg PH, Wisden W (March 1992). "The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. II. Olfactory bulb and cerebellum". The Journal of Neuroscience. 12 (3): 1063–1076. doi:10.1523/JNEUROSCI.12-03-01063.1992. PMC 6576040. PMID 1312132.
22. Faragó N, Kocsis ÁK, Lovas S, Molnár G, Boldog E, Rózsa M, et al. (June 2013). "Digital PCR to determine the number of transcripts from single neurons after patch-clamp recording". BioTechniques. 54 (6): 327–336. doi:10.2144/000114029. PMID 23750542.
23. Follesa P, Floris G, Asuni GP, Ibba A, Tocco MG, Zicca L, et al. (2015). "Chronic Intermittent Ethanol Regulates Hippocampal GABA(A) Receptor Delta Subunit Gene Expression". Frontiers in Cellular Neuroscience. 9: 445. doi:10.3389/fncel.2015.00445. PMC 4637418. PMID 26617492.
24. Mulligan MK, Wang X, Adler AL, Mozhui K, Lu L, Williams RW (2012). "Complex control of GABA(A) receptor subunit mRNA expression: variation, covariation, and genetic regulation". PLOS ONE. 7 (4): e34586. Bibcode:2012PLoSO...734586M. doi:10.1371/journal.pone.0034586. PMC 3323555. PMID 22506031.
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26. Schofield PR, Darlison MG, Fujita N, Burt DR, Stephenson FA, Rodriguez H, et al. (July 1987). "Sequence and functional expression of the GABA A receptor shows a ligand-gated receptor super-family". Nature. 328 (6127): 221–227. Bibcode:1987Natur.328..221S. doi:10.1038/328221a0. PMID 3037384. S2CID 4242202.
27. Seeburg PH, Wisden W, Verdoorn TA, Pritchett DB, Werner P, Herb A, et al. (1990-01-01). "The GABAA receptor family: molecular and functional diversity". Cold Spring Harbor Symposia on Quantitative Biology. 55: 29–40. doi:10.1101/SQB.1990.055.01.006. PMID 1966765.
28. Arslan A, von Engelhardt J, Wisden W (December 2014). "Cytoplasmic domain of δ subunit is important for the extra-synaptic targeting of GABAA receptor subtypes". Journal of Integrative Neuroscience. 13 (4): 617–631. doi:10.1142/S0219635214500228. PMID 25233879.
29. Christie SB, Li RW, Miralles CP, Yang B, De Blas AL (January 2006). "Clustered and non-clustered GABAA receptors in cultured hippocampal neurons". Molecular and Cellular Neurosciences. 31 (1): 1–14. doi:10.1016/j.mcn.2005.08.014. PMID 16181787. S2CID 40720887.
30. Oflaz FE, Son ÇD, Arslan A (December 2019). "Oligomerization and cell surface expression of recombinant GABAA receptors tagged in the δ subunit". Journal of Integrative Neuroscience. 18 (4): 341–350. doi:10.31083/j.jin.2019.04.1207. hdl:11511/41973. PMID 31912692. S2CID 210086414.
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Further reading

• Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, et al. (May 2006). "A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration". Cell. 125 (4): 801–814. doi:10.1016/j.cell.2006.03.032. PMID 16713569. S2CID 13709685.
• Lenzen KP, Heils A, Lorenz S, Hempelmann A, Sander T (June 2005). "Association analysis of the Arg220His variation of the human gene encoding the GABA delta subunit with idiopathic generalized epilepsy". Epilepsy Research. 65 (1–2): 53–57. doi:10.1016/j.eplepsyres.2005.04.005. PMID 16023832. S2CID 20661316.
• Windpassinger C, Kroisel PM, Wagner K, Petek E (June 2002). "The human gamma-aminobutyric acid A receptor delta (GABRD) gene: molecular characterisation and tissue-specific expression". Gene. 292 (1–2): 25–31. doi:10.1016/S0378-1119(02)00649-2. PMID 12119096.

External links

• GABRD+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.