GABA<sub>A</sub> receptor α2 subunit | GABA<sub>A</sub> receptors | IUPHAR/BPS Guide to PHARMACOLOGY

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GABAA receptor α2 subunit

Target not currently curated in GtoImmuPdb

Target id: 405

Nomenclature: GABAA receptor α2 subunit

Family: GABAA receptors

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Contents:

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 4 451 4p12 GABRA2 gamma-aminobutyric acid type A receptor subunit alpha2 7
Mouse 4 451 5 C3.1 Gabra2 gamma-aminobutyric acid (GABA) A receptor 10
Rat 4 - 14 Gabra2 gamma-aminobutyric acid type A receptor subunit alpha 2 10
Previous and Unofficial Names
gamma-aminobutyric acid receptor subunit alpha-2 | Gabra-2 | gamma-aminobutyric acid (GABA) A receptor, subunit alpha 2 | gamma-aminobutyric acid (GABA) A receptor | gamma-aminobutyric acid type A receptor alpha2 subunit
Database Links
CATH/Gene3D 2.70.170.10
ChEMBL Target CHEMBL4956 (Hs), CHEMBL2094133 (Mm), CHEMBL341 (Rn)
DrugBank Target P47869 (Hs), P47869 (Hs)
Ensembl Gene ENSG00000151834 (Hs), ENSMUSG00000000560 (Mm), ENSRNOG00000002349 (Rn)
Entrez Gene 2555 (Hs), 14395 (Mm), 29706 (Rn)
Human Protein Atlas ENSG00000151834 (Hs)
KEGG Gene hsa:2555 (Hs), mmu:14395 (Mm), rno:29706 (Rn)
OMIM 137140 (Hs)
Pharos P47869 (Hs)
RefSeq Nucleotide NM_000807 (Hs), NM_008066 (Mm), NM_001135779 (Rn)
RefSeq Protein NP_000798 (Hs), NP_032092 (Mm), NP_001129251 (Rn)
UniProtKB P47869 (Hs), P26048 (Mm), P23576 (Rn)
Wikipedia GABRA2 (Hs)
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
GABAA receptor β3 subunit
GABAA receptor γ2 subunit
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
Not determined
Associated Protein Comments
Heteromeric GABAA receptors can be formed from the proteins listed in the table above. These receptors generally consist of 2 α, 2 β and 1 γ subunit. An example of a GABAA receptor containing the α2 subunit is α2β3γ2.
Natural/Endogenous Ligands
GABA
5α-pregnan-3α-ol-20-one
tetrahydrodeoxycorticosterone
Zn2+

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 Value Parameter Reference
CGS8216 Hs Inverse agonist 10.1 pKi 8
⤷ pKi 10.1 (Ki 8x10-11 M) [8]
ZK93423 Hs Partial agonist 8.4 pKi 5
⤷ pKi 8.4 (Ki 4.2x10-9 M) [5]
[3H]muscimol Hs Agonist - -
⤷ [Binds to: GABA site]
isoguvacine Hs Full agonist - -
⤷ [Binds to: GABA site]
isonipecotic acid Hs Agonist - -
⤷ [Binds to: GABA site]
muscimol Hs Full agonist - -
⤷ [Binds to: GABA site]
piperidine-4-sulphonic acid Hs Full agonist - -
⤷ [Binds to: GABA site]
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 Value Parameter 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 Value Parameter 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 Value Parameter Concentration range (M) Voltage-dependent (mV) Reference
AZD7325 Hs Positive 9.5 pKi - no 3
⤷ pKi 9.5 (Ki 3x10-10 M) [3]
Not voltage dependent
triazolam Hs Positive 9.2 pKi - no 8
⤷ pKi 9.2 (Ki 5.9x10-10 M) [8]
Not voltage dependent
Description: Binding affinity to human recombinant GABAA receptor α2β3γ2.
flumazenil Hs Antagonist 9.1 pKi - no 9
⤷ pKi 9.1 (Ki 9x10-10 M) [Binds to: benzodiazepine site] [9]
Not voltage dependent
Description: Affinity measured using α2β3γ2 receptors.
clonazepam Hs Positive 8.8 pKi - no 12
⤷ pKi 8.8 (Ki 1.7x10-9 M) [12]
Not voltage dependent
Description: Assay using recombinant GABAA channels with subunit composition; α2β1γ2.
PF-06372865 Hs Positive >8.6 pKi - no 11
⤷ pKi >8.6 (Ki <2.47x10-9 M) [11]
Not voltage dependent
Description: Determined in a radioligand competition binding assay using [3H]flumazenil and recombinant human GABAA receptor with the α2/β2/γ3 configuration.
flunitrazepam Hs Positive 8.3 pKi - no 6
⤷ pKi 8.3 (Ki 5.2x10-9 M) [Binds to: benzodiazepine site] [6]
Not voltage dependent
Description: Assay using recombinant GABAA channels with subunit composition; α2β1γ2.
diazepam Hs Positive 7.8 pKi - no 12
⤷ pKi 7.8 (Ki 1.69x10-8 M) [Binds to: benzodiazepine site] [12]
Not voltage dependent
Description: Assay using recombinant GABAA channels with subunit composition; α2β1γ2.
zolpidem Hs Positive 6.1 pKi - no 7
⤷ pKi 6.1 (Ki 7.606x10-7 M) [7]
Not voltage dependent
Description: Assay using recombinant GABAA channels with subunit composition; α2β1γ2.
alprazolam Hs Positive 7.9 pEC50 - no 1
⤷ pEC50 7.9 (EC50 1.2x10-8 M) [Binds to: benzodiazepine site] [1]
Not voltage dependent
Zn2+ Hs Inhibition - - - no
⤷
Not voltage dependent
α3IA Hs Inverse agonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
α5IA Hs Inverse agonist - - - no
⤷ [Binds to: benzodiazepine site]
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
DMCM Hs Inverse agonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
L838417 Hs Partial agonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
MRK016 Hs Inverse agonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
ocinaplon Hs Partial agonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
Ro15-4513 Hs Inverse agonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
Ro19-4603 Hs Inverse agonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
RO4938581 Hs Inverse agonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
tetrahydrodeoxycorticosterone Hs Potentiation - - - no
⤷
Not voltage dependent
TP003 Hs Antagonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
TPA023 Hs Partial agonist - - - no
⤷ [Binds to: benzodiazepine site] low efficacy
Not voltage dependent
ZK93426 Hs Antagonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
[3H]flunitrazepam 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 Antagonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
[18F]fluoroethylflumazenil Hs Antagonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
Allosteric Modulator Comments
Alprazolam is an approved drug which is a positive allosteric modulator of the GABAA receptor. It has affinity for the benzodizepine site on several α subunits.
PF-06372865 enhances GABA-induced current by 124% in HEK cells expressing α2-containing receptors, but by only 18% in α1-containing receptors [11].
Clinically-Relevant Mutations and Pathophysiology
Disease:  Alcohol dependence
Disease Ontology: DOID:0050741
OMIM: 103780
Comments:  Polymorphisms in GABRA2 are associated with susceptibility to alcohol dependence
References:  2,4

References

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1. Albaugh PA, Marshall L, Gregory J, White G, Hutchison A, Ross PC, Gallagher DW, Tallman JF, Crago M, Cassella JV. (2002) Synthesis and biological evaluation of 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimdin-5(6H)-ones as functionally selective ligands of the benzodiazepine receptor site on the GABA(A) receptor. J. Med. Chem., 45 (23): 5043-51. [PMID:12408715]

2. Arias AJ, Covault J, Feinn R, Pond T, Yang BZ, Ge W, Oncken C, Kranzler HR. (2014) A GABRA2 variant is associated with increased stimulation and 'high' following alcohol administration. Alcohol Alcohol., 49 (1): 1-9. [PMID:24166645]

3. AstraZeneca. AZD7325. Accessed on 11/09/2014. Modified on 11/09/2014. astrazeneca.com, http://openinnovation.astrazeneca.com/what-we-offer/compound/azd7325/

4. Bierut LJ, Agrawal A, Bucholz KK, Doheny KF, Laurie C, Pugh E, Fisher S, Fox L, Howells W, Bertelsen S et al.. (2010) A genome-wide association study of alcohol dependence. Proc. Natl. Acad. Sci. U.S.A., 107 (11): 5082-7. [PMID:20202923]

5. Cox ED, Diaz-Arauzo H, Huang Q, Reddy MS, Ma C, Harris B, McKernan R, Skolnick P, Cook JM. (1998) Synthesis and evaluation of analogues of the partial agonist 6-(propyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (6-PBC) and the full agonist 6-(benzyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (Zk 93423) at wild type and recombinant GABAA receptors. J. Med. Chem., 41 (14): 2537-52. [PMID:9651158]

6. Hadingham KL, Garrett EM, Wafford KA, Bain C, Heavens RP, Sirinathsinghji DJ, Whiting PJ. (1996) Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors. Mol. Pharmacol., 49 (2): 253-9. [PMID:8632757]

7. Hadingham KL, Wingrove P, Le Bourdelles B, Palmer KJ, Ragan CI, Whiting PJ. (1993) Cloning of cDNA sequences encoding human alpha 2 and alpha 3 gamma-aminobutyric acidA receptor subunits and characterization of the benzodiazepine pharmacology of recombinant alpha 1-, alpha 2-, alpha 3-, and alpha 5-containing human gamma-aminobutyric acidA receptors. Mol. Pharmacol., 43 (6): 970-5. [PMID:8391122]

8. Huang Q, He X, Ma C, Liu R, Yu S, Dayer CA, Wenger GR, McKernan R, Cook JM. (2000) Pharmacophore/receptor models for GABA(A)/BzR subtypes (alpha1beta3gamma2, alpha5beta3gamma2, and alpha6beta3gamma2) via a comprehensive ligand-mapping approach. J. Med. Chem., 43 (1): 71-95. [PMID:10633039]

9. Huang Q, Liu R, Zhang P, He X, McKernan R, Gan T, Bennett DW, Cook JM. (1998) Predictive models for GABAA/benzodiazepine receptor subtypes: studies of quantitative structure-activity relationships for imidazobenzodiazepines at five recombinant GABAA/benzodiazepine receptor subtypes [alphaxbeta3gamma2 (x = 1-3, 5, and 6)] via comparative molecular field analysis. J. Med. Chem., 41 (21): 4130-42. [PMID:9767648]

10. Khrestchatisky M, MacLennan AJ, Tillakaratne NJ, Chiang MY, Tobin AJ. (1991) Sequence and regional distribution of the mRNA encoding the alpha 2 polypeptide of rat gamma-aminobutyric acidA receptors. J. Neurochem., 56 (5): 1717-22. [PMID:1849552]

11. Omoto K, Owen RM, Pryde DC, Watson CAL, Takeuchi M. (2014) Imidazopyridazine derivatives as GABAA receptor modulators. Patent number: WO2014091368. Assignee: Pfizer Limited. Priority date: 14/12/2012. Publication date: 19/06/2014.

12. Pritchett DB, Lüddens H, Seeburg PH. (1989) Type I and type II GABAA-benzodiazepine receptors produced in transfected cells. Science, 245 (4924): 1389-92. [PMID:2551039]

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