GABA<sub>A</sub> receptor α4 subunit | GABA<sub>A</sub> receptors | IUPHAR/BPS Guide to PHARMACOLOGY

GABAA receptor α4 subunit

Target id: 407

Nomenclature: GABAA receptor α4 subunit

Family: GABAA receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for GABAA receptor α4 subunit in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 4 554 4p12 GABRA4 gamma-aminobutyric acid type A receptor alpha4 subunit 7,14
Mouse 4 552 5 C3.2 Gabra4 gamma-aminobutyric acid (GABA) A receptor, subunit alpha 4 15
Rat 4 552 14p11 Gabra4 gamma-aminobutyric acid type A receptor alpha4 subunit 12
Previous and Unofficial Names
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
Database Links
CATH/Gene3D
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
GABA

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
[3H]muscimol Hs Full agonist - -
[Binds to: GABA site]
isoguvacine Hs Full agonist - -
[Binds to: GABA site]
isonipecotic acid Hs Full agonist - -
[Binds to: GABA site] relatively high efficacy
muscimol Hs Full agonist - -
[Binds to: GABA site]
piperidine-4-sulphonic acid Hs Full agonist - -
[Binds to: GABA site] low efficacy
gaboxadol Hs Agonist - -
[Binds to: GABA site]
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
bicuculline Hs Antagonist - -
[Binds to: GABA site]
[3H]gabazine Hs Antagonist - -
[Binds to: GABA site]
gabazine Hs Antagonist - -
[Binds to: GABA site]
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Use-dependent Affinity Units Concentration range (M) Voltage-dependent (mV) Reference
picrotoxin Hs - no - - - no

Not voltage dependent
TBPS Hs - no - - - no

Not voltage dependent
[35S]TBPS 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 Affinity Units Concentration range (M) Voltage-dependent (mV) Reference
flumazenil Rn Positive 7.0 pKi - no 11
pKi 7.0 (Ki 9.4x10-8 M) [11]
Not voltage dependent
Description: Antagonism of complexes containing α4β2γ2 subunits heterologously expressed in vitro.
Zn2+ Hs Inhibition - - - no

Not voltage dependent
5α-pregnan-3α-ol-20-one Hs Potentiation - - - no

Not voltage dependent
bretazenil Hs Full agonist - - - no
[Binds to: benzodiazepine site]
Not voltage dependent
Ro15-4513 Hs Full agonist - - - no
[Binds to: benzodiazepine site]
Not voltage dependent
tetrahydrodeoxycorticosterone Hs Potentiation - - - no

Not voltage dependent
[3H]Ro154513 Hs Full agonist - - - no
[Binds to: benzodiazepine site]
Not voltage dependent
[3H]CGS8216 Hs Mixed - - - no
[Binds to: benzodiazepine site] agonist and antagonist
Not voltage dependent
[11C]flumazenil Hs Partial agonist - - - no
[Binds to: benzodiazepine site] low affinity
Not voltage dependent
[18F]fluoroethylflumazenil Hs Antagonist - - - no
[Binds to: benzodiazepine site]
Not voltage dependent
View species-specific allosteric modulator tables
Tissue Distribution
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:  15
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:  13
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
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:  10
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:  10
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
Disease:  Autism
Synonyms: Autism spectrum disorder [Disease Ontology: DOID:0060041]
Disease Ontology: DOID:0060041
OMIM: 209850
Orphanet: ORPHA106
Role: 
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. U.S.A., 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. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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

Richard Olsen.
GABAA receptors: GABAA receptor α4 subunit. Last modified on 23/05/2017. Accessed on 14/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=407.