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GABAA receptor δ subunit

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Target id: 416

Nomenclature: GABAA receptor δ subunit

Family: GABAA receptors

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 4 452 1p36.33 GABRD gamma-aminobutyric acid type A receptor subunit delta 7,23
Mouse 4 449 4 E2 Gabrd gamma-aminobutyric acid (GABA) A receptor, subunit delta 23
Rat 4 449 5q36 Gabrd gamma-aminobutyric acid type A receptor subunit delta 21
Previous and Unofficial Names Click here for help
GABAA receptor delta subunit | gamma-aminobutyric acid (GABA) A receptor, delta | gamma-aminobutyric acid (GABA) A receptor, subunit delta | gamma-aminobutyric acid (GABA) A receptor | gamma-aminobutyric acid type A receptor delta subunit
Database Links Click here for help
Alphafold O14764 (Hs), P22933 (Mm), P18506 (Rn)
CATH/Gene3D 2.70.170.10
ChEMBL Target CHEMBL3591 (Hs), CHEMBL2094133 (Mm), CHEMBL4296056 (Rn), CHEMBL4296061 (Rn), CHEMBL4296050 (Rn), CHEMBL4296053 (Rn)
DrugBank Target O14764 (Hs), O14764 (Hs)
Ensembl Gene ENSG00000187730 (Hs), ENSMUSG00000029054 (Mm), ENSRNOG00000016385 (Rn)
Entrez Gene 2563 (Hs), 14403 (Mm), 29689 (Rn)
Human Protein Atlas ENSG00000187730 (Hs)
KEGG Gene hsa:2563 (Hs), mmu:14403 (Mm), rno:29689 (Rn)
OMIM 137163 (Hs)
Orphanet ORPHA121991 (Hs)
Pharos O14764 (Hs)
RefSeq Nucleotide NM_000815 (Hs), NM_008072 (Mm), NM_017289 (Rn)
RefSeq Protein NP_000806 (Hs), NP_032098 (Mm), NP_058985 (Rn)
UniProtKB O14764 (Hs), P22933 (Mm), P18506 (Rn)
Wikipedia GABRD (Hs)
Natural/Endogenous Ligands Click here for help
GABA

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
DS2 Small molecule or natural product Hs Agonist - - 22
⤷ [22]
gaboxadol Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist - -
⤷ [Binds to: GABA site]
tracazolate Small molecule or natural product Hs Agonist - - 22
⤷ [22]
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Use-dependent Value Parameter Concentration range (M) Voltage-dependent (mV) Reference
picrotoxin Small molecule or natural product Click here for species-specific activity table Hs - no - - - no
⤷
Not voltage dependent
TBPS Small molecule or natural product Click here for species-specific activity table Hs - no - - - no
⤷
Not voltage dependent
Tissue Distribution Click here for help
Dentate gyrus granule cells (located perisynaptically on dendrites)
Species:  Mouse
Technique:  Immunocytochemistry
References:  30
Hippocampal interneurons of the dentate molecular layer (assembles with the α1 subunit)
Species:  Mouse
Technique:  Immunohistochemistry, confocal microscopy
References:  9
Cerebellar granule cells (selective partnering with α6 subunit) shown by loss of δ protein, but not mRNA, in α6 subunit knockout mouse
Species:  Mouse
Technique:  Immunoprecipitation, immunocytochemistry, immunoblot analysis
References:  11
Thalamic relay nuclei, caudate-putamen, molecular layer of the dentate gyrus, and outer layers of the cerebral cortex
Species:  Mouse
Technique:  Immunohistochemistry
References:  17
Thalamus(assembles with the α4 subunit)
Species:  Rat
Technique:  Quantitative co-immunoprecipitation
References:  26
Cerebellar granule cells (restricted to extrasynaptic dendritic and somatic membranes)
Species:  Rat
Technique:  Immunohistochemistry
References:  16
Cerebellar granule cells, thalamus relay neurons, dentate gyrus granule cells, caudate-putamen, cortex, olfactory bulb (EP).
Species:  Rat
Technique:  Immunohistochemistry
References:  2,18,20
Medial geniculate thalamic nucleus (MGN)
Species:  Rat
Technique:  In situ hybridization and immunohistochemistry
References:  33
Physiological Consequences of Altering Gene Expression Click here for help
Mice lacking the δ subunit show reduced sensitivity to neuroactive steroids (Mihalek et al., 1999) and ethanol (Wei et al., 2004; Mihalek et al., 2001), and reduced inhibition in neurons normally expressing the δ subunit (Mihalek et al., 1999; Spigelman et al., 2003; Vicini et al., 2002; Porcello et al., 2003).
Species:  Mouse
Tissue: 
Technique:  Gene knockout
References:  13-14,19,24,27,29,31
Knockout females, but not males, show improved fear conditioning
Species:  Mouse
Tissue:  Nervous system
Technique:  Knockout
References:  15,31
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Chromosome 1p36 deletion syndrome
OMIM: 607872
Orphanet: ORPHA1606
References:  32
Disease:  Epilepsy, idiopathic generalized, susceptibility to, 10; EIG10
Synonyms: Generalized epilepsy with febrile seizures-plus [Orphanet: ORPHA36387] [Disease Ontology: DOID:0060170]
Idiopathic generalized epilepsy [Disease Ontology: DOID:1827]
Disease Ontology: DOID:1827, DOID:0060170
OMIM: 613060
Orphanet: ORPHA36387
Role:  A GABRD Glu177Ala variant is heterozygously associated with generalized epilepsy with febrile seizures plus (GEFS+)
References:  6
Disease:  Epilepsy, juvenile myoclonic, susceptibility to, 7; EJM7
Synonyms: Juvenile myoclonic epilepsy [Orphanet: ORPHA307] [Disease Ontology: DOID:4890]
Disease Ontology: DOID:4890
OMIM: 613060
Orphanet: ORPHA307
General Comments
Extrasynaptic δ subunit-containing GABAA receptors show distinct pharmacology, including low efficacy to GABA, and high sensitivity to positive modulation by neurosteroids [3,25], ethanol [10,12,28-29] and general anesthetics [1,4-5,8].

References

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1. Belelli D, Peden DR, Rosahl TW, Wafford KA, Lambert JJ. (2005) Extrasynaptic GABAA receptors of thalamocortical neurons: a molecular target for hypnotics. J Neurosci, 25 (50): 11513-20. [PMID:16354909]

2. Benke D, Mertens S, Trzeciak A, Gillessen D, Mohler H. (1991) Identification and immunohistochemical mapping of GABAA receptor subtypes containing the delta-subunit in rat brain. FEBS Lett, 283 (1): 145-9. [PMID:1645294]

3. Bianchi MT, Macdonald RL. (2003) Neurosteroids shift partial agonist activation of GABA(A) receptor channels from low- to high-efficacy gating patterns. J Neurosci, 23 (34): 10934-43. [PMID:14645489]

4. Brown N, Kerby J, Bonnert TP, Whiting PJ, Wafford KA. (2002) Pharmacological characterization of a novel cell line expressing human alpha(4)beta(3)delta GABA(A) receptors. Br J Pharmacol, 136 (7): 965-74. [PMID:12145096]

5. Caraiscos VB, Newell JG, You-Ten KE, Elliott EM, Rosahl TW, Wafford KA, MacDonald JF, Orser BA. (2004) Selective enhancement of tonic GABAergic inhibition in murine hippocampal neurons by low concentrations of the volatile anesthetic isoflurane. J Neurosci, 24 (39): 8454-8. [PMID:15456818]

6. Dibbens LM, Feng HJ, Richards MC, Harkin LA, Hodgson BL, Scott D, Jenkins M, Petrou S, Sutherland GR, Scheffer IE, Berkovic SF, Macdonald RL, Mulley JC. (2004) GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Hum Mol Genet, 13 (13): 1315-9. [PMID:15115768]

7. Emberger W, Windpassinger C, Petek E, Kroisel PM, Wagner K. (2000) Assignment of the human GABAA receptor delta-subunit gene (GABRD) to chromosome band 1p36.3 distal to marker NIB1364 by radiation hybrid mapping. Cytogenet Cell Genet, 89 (3-4): 281-2. [PMID:10965146]

8. Feng HJ, Bianchi MT, Macdonald RL. (2004) Pentobarbital differentially modulates alpha1beta3delta and alpha1beta3gamma2L GABAA receptor currents. Mol Pharmacol, 66 (4): 988-1003. [PMID:15247320]

9. Glykys J, Peng Z, Chandra D, Homanics GE, Houser CR, Mody I. (2007) A new naturally occurring GABA(A) receptor subunit partnership with high sensitivity to ethanol. Nat Neurosci, 10 (1): 40-8. [PMID:17159992]

10. Hanchar HJ, Dodson PD, Olsen RW, Otis TS, Wallner M. (2005) Alcohol-induced motor impairment caused by increased extrasynaptic GABA(A) receptor activity. Nat Neurosci, 8 (3): 339-45. [PMID:15696164]

11. Jones A, Korpi ER, McKernan RM, Pelz R, Nusser Z, Mäkelä R, Mellor JR, Pollard S, Bahn S, Stephenson FA, Randall AD, Sieghart W, Somogyi P, Smith AJ, Wisden W. (1997) Ligand-gated ion channel subunit partnerships: GABAA receptor alpha6 subunit gene inactivation inhibits delta subunit expression. J Neurosci, 17 (4): 1350-62. [PMID:9006978]

12. Liang J, Zhang N, Cagetti E, Houser CR, Olsen RW, Spigelman I. (2006) Chronic intermittent ethanol-induced switch of ethanol actions from extrasynaptic to synaptic hippocampal GABAA receptors. J Neurosci, 26 (6): 1749-58. [PMID:16467523]

13. Mihalek RM, Banerjee PK, Korpi ER, Quinlan JJ, Firestone LL, Mi ZP, Lagenaur C, Tretter V, Sieghart W, Anagnostaras SG, Sage JR, Fanselow MS, Guidotti A, Spigelman I, Li Z, DeLorey TM, Olsen RW, Homanics GE. (1999) Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knockout mice. Proc Natl Acad Sci USA, 96 (22): 12905-10. [PMID:10536021]

14. Mihalek RM, Bowers BJ, Wehner JM, Kralic JE, VanDoren MJ, Morrow AL, Homanics GE. (2001) GABA(A)-receptor delta subunit knockout mice have multiple defects in behavioral responses to ethanol. Alcohol Clin Exp Res, 25 (12): 1708-18. [PMID:11781502]

15. Moore MD, Cushman J, Chandra D, Homanics GE, Olsen RW, Fanselow MS. (2010) Trace and contextual fear conditioning is enhanced in mice lacking the alpha4 subunit of the GABA(A) receptor. Neurobiol Learn Mem, 93 (3): 383-7. [PMID:20018248]

16. Nusser Z, Sieghart W, Somogyi P. (1998) Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells. J Neurosci, 18 (5): 1693-703. [PMID:9464994]

17. Peng Z, Hauer B, Mihalek RM, Homanics GE, Sieghart W, Olsen RW, Houser CR. (2002) GABA(A) receptor changes in delta subunit-deficient mice: altered expression of alpha4 and gamma2 subunits in the forebrain. J Comp Neurol, 446 (2): 179-97. [PMID:11932935]

18. Pirker S, Schwarzer C, Wieselthaler A, Sieghart W, Sperk G. (2000) GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience, 101 (4): 815-50. [PMID:11113332]

19. Porcello DM, Huntsman MM, Mihalek RM, Homanics GE, Huguenard JR. (2003) Intact synaptic GABAergic inhibition and altered neurosteroid modulation of thalamic relay neurons in mice lacking delta subunit. J Neurophysiol, 89 (3): 1378-86. [PMID:12626617]

20. Schwarzer C, Berresheim U, Pirker S, Wieselthaler A, Fuchs K, Sieghart W, Sperk G. (2001) Distribution of the major gamma-aminobutyric acid(A) receptor subunits in the basal ganglia and associated limbic brain areas of the adult rat. J Comp Neurol, 433 (4): 526-49. [PMID:11304716]

21. Shivers BD, Killisch I, Sprengel R, Sontheimer H, Köhler M, Schofield PR, Seeburg PH. (1989) Two novel GABAA receptor subunits exist in distinct neuronal subpopulations. Neuron, 3 (3): 327-37. [PMID:2561970]

22. Sieghart W, Savić MM. (2018) International Union of Basic and Clinical Pharmacology. CVI: GABAA Receptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans. Pharmacol Rev, 70 (4): 836-878. [PMID:30275042]

23. Sommer B, Poustka A, Spurr NK, Seeburg PH. (1990) The murine GABAA receptor delta-subunit gene: structure and assignment to human chromosome 1. DNA Cell Biol, 9 (8): 561-8. [PMID:2176788]

24. Spigelman I, Li Z, Liang J, Cagetti E, Samzadeh S, Mihalek RM, Homanics GE, Olsen RW. (2003) Reduced inhibition and sensitivity to neurosteroids in hippocampus of mice lacking the GABA(A) receptor delta subunit. J Neurophysiol, 90 (2): 903-10. [PMID:12702713]

25. Stell BM, Brickley SG, Tang CY, Farrant M, Mody I. (2003) Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by delta subunit-containing GABAA receptors. Proc Natl Acad Sci USA, 100 (24): 14439-44. [PMID:14623958]

26. Sur C, Farrar SJ, Kerby J, Whiting PJ, Atack JR, McKernan RM. (1999) Preferential coassembly of alpha4 and delta subunits of the gamma-aminobutyric acidA receptor in rat thalamus. Mol Pharmacol, 56 (1): 110-5. [PMID:10385690]

27. Vicini S, Losi G, Homanics GE. (2002) GABA(A) receptor delta subunit deletion prevents neurosteroid modulation of inhibitory synaptic currents in cerebellar neurons. Neuropharmacology, 43 (4): 646-50. [PMID:12367609]

28. Wallner M, Hanchar HJ, Olsen RW. (2003) Ethanol enhances alpha 4 beta 3 delta and alpha 6 beta 3 delta gamma-aminobutyric acid type A receptors at low concentrations known to affect humans. Proc Natl Acad Sci USA, 100 (25): 15218-23. [PMID:14625373]

29. Wei W, Faria LC, Mody I. (2004) Low ethanol concentrations selectively augment the tonic inhibition mediated by delta subunit-containing GABAA receptors in hippocampal neurons. J Neurosci, 24 (38): 8379-82. [PMID:15385620]

30. Wei W, Zhang N, Peng Z, Houser CR, Mody I. (2003) Perisynaptic localization of delta subunit-containing GABA(A) receptors and their activation by GABA spillover in the mouse dentate gyrus. J Neurosci, 23 (33): 10650-61. [PMID:14627650]

31. Wiltgen BJ, Sanders MJ, Ferguson C, Homanics GE, Fanselow MS. (2005) Trace fear conditioning is enhanced in mice lacking the delta subunit of the GABAA receptor. Learn Mem, 12 (3): 327-33. [PMID:15897254]

32. Windpassinger C, Kroisel PM, Wagner K, Petek E. (2002) The human gamma-aminobutyric acid A receptor delta (GABRD) gene: molecular characterisation and tissue-specific expression. Gene, 292 (1-2): 25-31. [PMID:12119096]

33. Wisden W, Laurie DJ, Monyer H, Seeburg PH. (1992) The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon. J Neurosci, 12 (3): 1040-62. [PMID:1312131]

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