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GABAA receptor α4 subunit

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Target not currently curated in GtoImmuPdb

Target id: 407

Nomenclature: GABAA receptor α4 subunit

Family: GABAA receptors

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 4 554 4p12 GABRA4 gamma-aminobutyric acid type A receptor subunit alpha4 7,16
Mouse 4 552 5 C3.1-C3.2 Gabra4 gamma-aminobutyric acid type A receptor subunit alpha 4 17
Rat 4 552 14p11 Gabra4 gamma-aminobutyric acid type A receptor subunit alpha 4 14
Previous and Unofficial Names Click here for help
gamma-aminobutyric acid receptor subunit alpha-4 | Gabra-4 | gamma-aminobutyric acid (GABA) A receptor, alpha 4 | gamma-aminobutyric acid (GABA) A receptor, subunit alpha 4 | gamma-aminobutyric acid (GABA) A receptor | gamma-aminobutyric acid type A receptor alpha4 subunit
Database Links Click here for help
Alphafold P48169 (Hs), Q9D6F4 (Mm), P28471 (Rn)
CATH/Gene3D 2.70.170.10
ChEMBL Target CHEMBL2472 (Hs), CHEMBL2094133 (Mm), CHEMBL292 (Rn)
DrugBank Target P48169 (Hs), P48169 (Hs)
Ensembl Gene ENSG00000109158 (Hs), ENSMUSG00000029211 (Mm), ENSRNOG00000002336 (Rn)
Entrez Gene 2557 (Hs), 14397 (Mm), 140675 (Rn)
Human Protein Atlas ENSG00000109158 (Hs)
KEGG Gene hsa:2557 (Hs), mmu:14397 (Mm), rno:140675 (Rn)
OMIM 137141 (Hs)
Pharos P48169 (Hs)
RefSeq Nucleotide NM_000809 (Hs), NM_010251 (Mm), NM_080587 (Rn)
RefSeq Protein NP_000800 (Hs), NP_034381 (Mm), NP_542154 (Rn)
UniProtKB P48169 (Hs), Q9D6F4 (Mm), P28471 (Rn)
Wikipedia GABRA4 (Hs)
Natural/Endogenous Ligands Click here for help
GABA
5α-pregnan-3α-ol-20-one
tetrahydrodeoxycorticosterone
Zn2+

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand
Sp.
Action
[3H]muscimol Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Full agonist - -
⤷ [Binds to: GABA site]
isoguvacine Small molecule or natural product Click here for species-specific activity table Hs Full agonist - -
⤷ [Binds to: GABA site]
isonipecotic acid Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist - -
⤷ [Binds to: GABA site] relatively high efficacy, partially selective
muscimol Small molecule or natural product Click here for species-specific activity table Hs Full agonist - -
⤷ [Binds to: GABA site]
piperidine-4-sulphonic acid Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist - -
⤷ [Binds to: GABA site] low efficacy
gaboxadol Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Agonist - -
⤷ [Binds to: GABA site]
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand
Sp.
Action
bicuculline Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist - -
⤷ [Binds to: GABA site]
[3H]gabazine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist - -
⤷ [Binds to: GABA site]
gabazine Small molecule or natural product Click here for species-specific activity table Hs Antagonist - -
⤷ [Binds to: GABA site]
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand
Sp.
Use-dependent
Voltage-dependent (mV)
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
[35S]TBPS Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs - no - - - no
⤷ [Binds to: anion channel]
Not voltage dependent
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand
Sp.
Action
Value
Parameter
Voltage-dependent (mV)
Reference
flumazenil Small molecule or natural product Approved drug Ligand has a PDB structure Rn Positive 7.0 pKi - no 13
⤷ pKi 7.0 (Ki 9.4x10-8 M) Antagonist at α1 receptors, but allosteric modulator at other subtypes. [13]
Not voltage dependent
Description: Antagonism of complexes containing α4β2γ2 subunits heterologously expressed in vitro.
cenobamate Small molecule or natural product Approved drug Click here for species-specific activity table Hs Positive 4.4 pEC50 - no 12
⤷ pEC50 4.4 (EC50 4.2x10-5 M) [12]
Not voltage dependent
Description: Allosteric modulation of GABA-activated human α4β3γ2 GABAA channels expressed in HEK cells.
Zn2+ Click here for species-specific activity table Ligand is endogenous in the given species Hs Inhibition - - - no
⤷
Not voltage dependent
5α-pregnan-3α-ol-20-one Small molecule or natural product Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Potentiation - - - no
⤷
Not voltage dependent
bretazenil Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist - - - no 10
⤷ [Binds to: benzodiazepine site] [10]
Not voltage dependent
Ro15-4513 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
tetrahydrodeoxycorticosterone Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Potentiation - - - no
⤷
Not voltage dependent
[3H]Ro154513 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Ligand has a PDB structure Hs Full agonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
[3H]CGS8216 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Mixed - - - no
⤷ [Binds to: benzodiazepine site] agonist and antagonist
Not voltage dependent
[11C]flumazenil Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Ligand has a PDB structure Hs Partial agonist - - - no
⤷ [Binds to: benzodiazepine site] low affinity
Not voltage dependent
[18F]fluoroethylflumazenil Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs - - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
View species-specific allosteric modulator tables
Tissue Distribution Click here for help
Thalamus, striatum, molecular layer of the dentate gyrus, cerebral cortex and CA1 field of the hippocampus
Species:  Mouse
Technique:  Immunohistochemistry
References:  2
Thalamus (except the ventral lateral geniculate, reticular and central medial thalamic nuclei), striatum, nucleus accumbens, tuberculum olfactorium, molecular layer of the dentate gyrus, outer layers of the cerebral cortex, CA1 sector of the hippocampus, septum outer layers of the colliculus superior, entire brainstem
Species:  Rat
Technique:  Immunocytochemistry
References:  9
Cerebral cortex, anterior olfactory nucleus, lateral septum, subiculum, lateral and medial nuclei of the amygdaloid complex, anterior nuclei of the thalamus, pars compacta of the substantia nigra, trigeminal sensory nuclei, cochlear nucleus, granular cell layer of the olfactory bulb, caudate-putamen, tenia tecta, pyramidal cell layer of the CA region and granular cell layer of the dentate gyrus of the hippocampal formation, dorsomedial and ventrolateral nuclei of the thalamus, dorsal lateral geniculate body, preolivary nuclei, pontine nuclei
Species:  Rat
Technique:  In situ hybridisation
References:  1
Thalamic nuclei, hippocampus, caudate putamen, cerebral cortex
Species:  Rat
Technique:  In situ hybridisation histochemistry
References:  17
Thalamic nuclei, granule cells of the olfactory bulb, neocortex and pyriform cortex, CA1, CA3 and dentate granule cells of the hippocampus, tenia tecta, caudate putamen, nucleus accumbens, claustrum, medial and lateral amygdala, septum
Species:  Rat
Technique:  In situ hybridisation histochemistry
References:  15
All thalamic nuclei except the intralaminar nuclei
Species:  Rhesus macaque
Technique: 
References:  4
Tissue Distribution Comments
In situ hybrisation histochemistry experiments in tissues from two additional monkey species, Macaca fuscata, and Macaca fascicularis, also revealed the GABA A α4 subunit to be present in thalamic nuclei.
Physiological Consequences of Altering Gene Expression Click here for help
Mice lacking the α4 subunit superficially resemble their wild-type littermates. However, in knockout animals tonic inhibition mediated by GABA in dentate granule cells and thalamic relay neurons is absent and mIPSP kinetics are slowed. Knockout mice are insensitive to the ataxic, sedative, and analgesic effects of gaboxadol (THIP) which displays high efficacy as an agonist at GABAA receptors containing the α4 subunit.
Species:  Mouse
Tissue:  Nervous
Technique:  Knockout
References:  2,5
Mice lacking the α4 subunit exhibit a reduced amnestic effect of the general anaesthetic isoflurane, but loss of righting reflex is minimally affected, and immobility induced by the agent is unchanged.
Species:  Mouse
Tissue:  Nervous
Technique:  Knockout
References:  11
A reduction in the expression of the α4 subunit (mediated by RNAi) in the nucleus accumbens shell of rats decreases their free consumption of and preference for alcohol. The reduction in drinking is region- and alcohol-specific: reduced expression of the α4 subunit in the nucleus accumbens core does not affect alcohol intake and reduced expression of the subunit in the nucleus accumbens shell does not alter sucrose, or water, intake.
Species:  Rat
Tissue:  Nucleus accumbens
Technique:  RNAi
References:  11
α4 subunit knockout mice show enhanced trace and contextual fear conditioning in a manner that is sex dependent.
Species:  Mouse
Tissue:  Nervous
Technique:  Knockout
References:  8
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Autism
Synonyms: Autism spectrum disorder [Disease Ontology: DOID:0060041]
Disease Ontology: DOID:0060041
OMIM: 209850
Orphanet: ORPHA106
Role:  Several SNPs in the GABRA4 gene (i.e. rs1912960, rs17599165, rs17599416, rs2280073 and rs16859788) associate with autism.
References:  3,6

References

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1. Araki T, Tohyama M. (1992) Region-specific expression of GABAA receptor alpha 3 and alpha 4 subunits mRNAs in the rat brain. Brain Res Mol Brain Res, 12 (4): 293-314. [PMID:1315904]

2. Chandra D, Jia F, Liang J, Peng Z, Suryanarayanan A, Werner DF, Spigelman I, Houser CR, Olsen RW, Harrison NL et al.. (2006) GABAA receptor alpha 4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol. Proc Natl Acad Sci USA, 103 (41): 15230-5. [PMID:17005728]

3. Collins AL, Ma D, Whitehead PL, Martin ER, Wright HH, Abramson RK, Hussman JP, Haines JL, Cuccaro ML, Gilbert JR et al.. (2006) Investigation of autism and GABA receptor subunit genes in multiple ethnic groups. Neurogenetics, 7 (3): 167-74. [PMID:16770606]

4. Huntsman MM, Leggio MG, Jones EG. (1996) Nucleus-specific expression of GABA(A) receptor subunit mRNAs in monkey thalamus. J Neurosci, 16 (11): 3571-89. [PMID:8642403]

5. Liang J, Suryanarayanan A, Chandra D, Homanics GE, Olsen RW, Spigelman I. (2008) Functional consequences of GABAA receptor alpha 4 subunit deletion on synaptic and extrasynaptic currents in mouse dentate granule cells. Alcohol Clin Exp Res, 32 (1): 19-26. [PMID:18070250]

6. Ma DQ, Whitehead PL, Menold MM, Martin ER, Ashley-Koch AE, Mei H, Ritchie MD, Delong GR, Abramson RK, Wright HH et al.. (2005) Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism. Am J Hum Genet, 77 (3): 377-88. [PMID:16080114]

7. McLean PJ, Farb DH, Russek SJ. (1995) Mapping of the alpha 4 subunit gene (GABRA4) to human chromosome 4 defines an alpha 2-alpha 4-beta 1-gamma 1 gene cluster: further evidence that modern GABAA receptor gene clusters are derived from an ancestral cluster. Genomics, 26 (3): 580-6. [PMID:7607683]

8. 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]

9. 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]

10. Ramerstorfer J, Furtmüller R, Vogel E, Huck S, Sieghart W. (2010) The point mutation gamma 2F77I changes the potency and efficacy of benzodiazepine site ligands in different GABAA receptor subtypes. Eur J Pharmacol, 636 (1-3): 18-27. [PMID:20303942]

11. Rewal M, Jurd R, Gill TM, He DY, Ron D, Janak PH. (2009) Alpha4-containing GABAA receptors in the nucleus accumbens mediate moderate intake of alcohol. J Neurosci, 29 (2): 543-9. [PMID:19144854]

12. Sharma R, Nakamura M, Neupane C, Jeon BH, Shin H, Melnick SM, Glenn KJ, Jang IS, Park JB. (2020) Positive allosteric modulation of GABAA receptors by a novel antiepileptic drug cenobamate. Eur J Pharmacol, 879: 173117. [PMID:32325146]

13. Wieland HA, Lüddens H. (1994) Four amino acid exchanges convert a diazepam-insensitive, inverse agonist-preferring GABAA receptor into a diazepam-preferring GABAA receptor. J Med Chem, 37 (26): 4576-80. [PMID:7799410]

14. Wisden W, Herb A, Wieland H, Keinänen K, Lüddens H, Seeburg PH. (1991) Cloning, pharmacological characteristics and expression pattern of the rat GABAA receptor alpha 4 subunit. FEBS Lett, 289 (2): 227-30. [PMID:1655526]

15. 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]

16. Yang W, Drewe JA, Lan NC. (1995) Cloning and characterization of the human GABAA receptor alpha 4 subunit: identification of a unique diazepam-insensitive binding site. Eur J Pharmacol, 291 (3): 319-25. [PMID:8719416]

17. Ymer S, Draguhn A, Köhler M, Schofield PR, Seeburg PH. (1989) Sequence and expression of a novel GABAA receptor alpha subunit. FEBS Lett, 258 (1): 119-22. [PMID:2556293]

Contributors

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How to cite this page

Belelli D, Hales TG, Lambert JJ, Luscher B, Olsen R, Peters JA, Rudolph U, Sieghart W. GABAA receptors in GtoPdb v.2023.1. IUPHAR/BPS Guide to Pharmacology CITE. 2023; 2023(1). Available from: https://doi.org/10.2218/gtopdb/F72/2023.1.