Biology:GABRD

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Gamma-aminobutyric acid receptor subunit delta is a protein that in humans is encoded by the GABRD gene.[1][2][3] 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).[4]

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,[4][5] 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).[6][5] The GABRD gene encodes the delta (δ) subunit.[3] Specifically, the δ-subunit is usually expressed in GABAA receptors associated with extrasynaptic activity, mediating tonic inhibition, which is slower compared to classical inhibition (phasic or synaptic inhibition).[5] The most common GABAA receptors have the gamma subunit, which allows the receptor to bind benzodiazepines. 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.[4] 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.[7]

Clinical signifance

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.[8][9]

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.[10]

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.[11]

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.[12]

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.[13] 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.[14] 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.[15]

Tissue distribution

The cellular localization of mRNAs of 13 GABAA receptor subunits was analyzed in different brain regions.[16] 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 GABAA receptor subtypes.[17] 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[4]
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.[18] Gene expression was detected in all three cell types, but showed marked enrichment in neurogliaform cells versus the other cell types examined.[18] The GABAA receptor delta subunit is profoundly downregulated with chronic intermittent exposure to ethanol, and appears to contribute strongly to pathological alcohol dependence.[19]

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.[20]

Cloning

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.[5][21][22] 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.[23]

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.[24][25][26] 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.[26] However, another group suggested that the δ subunit can target to the cell membrane and the βδ containing receptors exist.[27]

See also

References

  1. ↑ "The murine GABAA receptor delta-subunit gene: structure and assignment to human chromosome 1". DNA and Cell Biology 9 (8): 561–568. October 1990. doi:10.1089/dna.1990.9.561. PMID 2176788. 
  2. ↑ "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. Sep 2000. doi:10.1159/000015636. PMID 10965146. 
  3. ↑ 3.0 3.1 "Entrez Gene: GABRD gamma-aminobutyric acid (GABA) A receptor, delta". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2563. 
  4. ↑ 4.0 4.1 4.2 4.3 "Extrasynaptic δ-subunit containing GABAA receptors". Journal of Integrative Neuroscience 20 (1): 173–184. March 2021. doi:10.31083/j.jin.2021.01.284. PMID 33834705. 
  5. ↑ 5.0 5.1 5.2 5.3 "GABAA receptors: Structure and function in the basal ganglia". GABA(A) receptors: structure and function in the basal ganglia. Progress in Brain Research. 160. Elsevier. 2007. pp. 21–41. doi:10.1016/s0079-6123(06)60003-4. ISBN 978-0-444-52184-2. 
  6. ↑ "Drug interactions at GABA(A) receptors". Progress in Neurobiology 67 (2): 113–159. June 2002. doi:10.1016/S0301-0082(02)00013-8. PMID 12126658. 
  7. ↑ "GABAA receptor drugs and neuronal plasticity in reward and aversion: focus on the ventral tegmental area". Frontiers in Pharmacology 5: 256. 2014-11-25. doi:10.3389/fphar.2014.00256. PMID 25505414. 
  8. ↑ "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. July 2004. doi:10.1093/hmg/ddh146. PMID 15115768. 
  9. ↑ "Role of GABRD Gene Methylation in the Nucleus Accumbens in Heroin-Seeking Behavior in Rats". Frontiers in Pharmacology 11: 612200. 2020. doi:10.3389/fphar.2020.612200. PMID 33551813. 
  10. ↑ "Loss of Gabrd in CRH neurons blunts the corticosterone response to stress and diminishes stress-related behaviors". Psychoneuroendocrinology 41: 75–88. March 2014. doi:10.1016/j.psyneuen.2013.12.011. PMID 24495609. 
  11. ↑ "Association of GABAA Receptor Gene with Epilepsy Syndromes". Journal of Molecular Neuroscience 65 (2): 141–153. June 2018. doi:10.1007/s12031-018-1081-7. PMID 29785705. 
  12. ↑ "Association of the GABRD gene and childhood-onset mood disorders". Genes, Brain, and Behavior 9 (6): 668–672. August 2010. doi:10.1111/j.1601-183X.2010.00598.x. PMID 20561060. 
  13. ↑ "GABRD promotes progression and predicts poor prognosis in colorectal cancer". Open Medicine 15 (1): 1172–1183. 2020. doi:10.1515/med-2020-0128. PMID 33336074. 
  14. ↑ "Gain-of-function variants in GABRD reveal a novel pathway for neurodevelopmental disorders and epilepsy". Brain 145 (4): 1299–1309. May 2022. doi:10.1093/brain/awab391. PMID 34633442. 
  15. ↑ "Enhanced expression of GABRD predicts poor prognosis in patients with colon adenocarcinoma". Translational Oncology 13 (12): 100861. December 2020. doi:10.1016/j.tranon.2020.100861. PMID 32891902. 
  16. ↑ "The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon". The Journal of Neuroscience 12 (3): 1040–1062. March 1992. doi:10.1523/JNEUROSCI.12-03-01040.1992. PMID 1312131. 
  17. ↑ "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. March 1992. doi:10.1523/JNEUROSCI.12-03-01063.1992. PMID 1312132. 
  18. ↑ 18.0 18.1 "Digital PCR to determine the number of transcripts from single neurons after patch-clamp recording". BioTechniques 54 (6): 327–336. June 2013. doi:10.2144/000114029. PMID 23750542. 
  19. ↑ "Chronic Intermittent Ethanol Regulates Hippocampal GABA(A) Receptor Delta Subunit Gene Expression". Frontiers in Cellular Neuroscience 9: 445. 2015. doi:10.3389/fncel.2015.00445. PMID 26617492. 
  20. ↑ "Complex control of GABA(A) receptor subunit mRNA expression: variation, covariation, and genetic regulation". PLOS ONE 7 (4): e34586. 2012. doi:10.1371/journal.pone.0034586. PMID 22506031. Bibcode: 2012PLoSO...734586M. 
  21. ↑ "Glycine vs GABA receptors". Nature 330 (6143): 25–26. November 1987. doi:10.1038/330025b0. PMID 2823147. Bibcode: 1987Natur.330...25G. 
  22. ↑ "Sequence and functional expression of the GABA A receptor shows a ligand-gated receptor super-family". Nature 328 (6127): 221–227. July 1987. doi:10.1038/328221a0. PMID 3037384. Bibcode: 1987Natur.328..221S. 
  23. ↑ "The GABAA receptor family: molecular and functional diversity". Cold Spring Harbor Symposia on Quantitative Biology 55: 29–40. 1990-01-01. doi:10.1101/SQB.1990.055.01.006. PMID 1966765. 
  24. ↑ "Cytoplasmic domain of δ subunit is important for the extra-synaptic targeting of GABAA receptor subtypes". Journal of Integrative Neuroscience 13 (4): 617–631. December 2014. doi:10.1142/S0219635214500228. PMID 25233879. 
  25. ↑ "Clustered and non-clustered GABAA receptors in cultured hippocampal neurons". Molecular and Cellular Neurosciences 31 (1): 1–14. January 2006. doi:10.1016/j.mcn.2005.08.014. PMID 16181787. 
  26. ↑ 26.0 26.1 "Oligomerization and cell surface expression of recombinant GABAA receptors tagged in the δ subunit". Journal of Integrative Neuroscience 18 (4): 341–350. December 2019. doi:10.31083/j.jin.2019.04.1207. PMID 31912692. 
  27. ↑ "A pharmacological characterization of GABA, THIP and DS2 at binary α4β3 and β3δ receptors: GABA activates β3δ receptors via the β3(+)δ(-) interface". Brain Research 1644: 222–230. August 2016. doi:10.1016/j.brainres.2016.05.019. PMID 27181518. 

Further reading

External links

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



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