GABAA Receptors

GABAA receptors are members of the Cys-loop family of ligand-gated ion channels and are permeable to Cl-. Activation of these receptors results in influx of Cl- into a neuron and hyperpolarization of the cell membrane, making it more difficult for the neuron to conduct an action potential. Endogenous GABAA receptors display large functional and pharmacological heterogeneity due to the existence of multiple subunits, subunit subtypes and splice variants of subunit subtypes.

Products
Background
Literature (7)
Gene Data

Agonists

Cat. No. Product Name / Activity
0344 GABA
Endogenous agonist
0235 Isoguvacine hydrochloride
Selective GABAA agonist
3250 L-838,417
GABAA partial agonist; displays subtype selectivity
4415 MK 0343
GABAA partial agonist; displays subtype selectivity
0289 Muscimol
Potent GABAA agonist; also GABAA-ρ partial agonist
4709 RuBi GABA trimethylphosphine
Caged GABA; inhibits neural activity
0181 TACA
GABAA agonist; also GABA-T substrate and GABA uptake inhibitor
0807 THIP hydrochloride
GABAA agonist
0180 ZAPA sulfate
'Low affinity' GABAA agonist; also GABAA-ρ antagonist

Inverse Agonists

Cat. No. Product Name / Activity
3817 MRK 016
α5-selective GABAA inverse agonist
2905 TB 21007
α5-selective GABAA inverse agonist

Antagonists

Cat. No. Product Name / Activity
2503 (-)-Bicuculline methiodide
GABAA antagonist; more water soluble version of (+)-bicuculline (Cat. No. 0130)
0109 (-)-Bicuculline methobromide
GABAA antagonist; more water soluble version of (+)-bicuculline (Cat. No. 0130)
0131 (-)-Bicuculline methochloride
GABAA antagonist; more water soluble version of (+)-bicuculline (Cat. No. 0130)
0130 (+)-Bicuculline
Potent GABAA antagonist
3109 Furosemide
GABAA antagonist; also Na+/2Cl-/K+ cotransporter blocker
4466 PHP 501 trifluoroacetate
Potent GABAA antagonist
1128 Picrotoxin
GABAA antagonist
2143 SCS
Potent GABAA antagonist; β1-subunit selective
1262 SR 95531 hydrobromide
Competitive and selective GABAA antagonist
2745 U 93631
GABAA antagonist

Benzodiazepines

Cat. No. Product Name / Activity
3568 Bretazenil
Benzodiazepine partial agonist
0405 β-CCB
Benzodiazepine inverse agonist; putative endogenous ligand
2467 CGS 20625
Selective benzodiazepine partial agonist
0456 Chlormezanone
Positive allosteric modulator of benzodiazepine site
1709 CL 218872
Benzodiazepine agonist
2805 Diazepam
Acts at the benzodiazepine modulatory site
0505 Dihydroergotoxine mesylate
Binds to GABAA receptor Cl- channel; allosteric modulator of benzodiazepine site
3083 DMCM hydrochloride
Benzodiazepine inverse agonist
0554 FG 7142
Benzodiazepine inverse agonist
0658 FGIN-1-27
Potent ligand for mitochondrial DBI receptor; GABAA receptor modulator
0659 FGIN-1-43
Potent ligand for mitochondrial DBI receptor; GABAA receptor modulator
1328 Flumazenil
Benzodiazepine antagonist
2174 Hispidulin
Partial positive allosteric modulator at the benzodiazepine site
3597 Indiplon
Positive allosteric modulator of GABAA; acts at benzodiazepine site
1327 L-655,708
Benzodiazepine inverse agonist; selective for α5-containing GABAA receptors
2832 Midazolam hydrochloride
Benzodiazepine agonist
1997 Ro 15-4513
Benzodiazepine partial inverse agonist
3942 TCS 1105
GABAA α2 benzodiazepine agonist
4414 TP 003
GABAA partial agonist; acts at benzodiazepine site
1994 ZK 93423 hydrochloride
Potent benzodiazepine agonist
1996 ZK 93426 hydrochloride
Potent and competitive benzodiazepine antagonist

Modulators

Cat. No. Product Name / Activity
3972 AA 29504
Positive allosteric modulator of GABAA receptors
3653 Allopregnanolone
Positive allosteric modulator of GABAA receptors
0881 Chlormethiazole hydrochloride
Potentiates GABAA receptor function
3679 DS2
Positive allosteric modulator of GABAA receptors; displays subunit selectivity
3113 Etifoxine hydrochloride
GABAA potentiator; anxiolytic
1471 Etomidate
GABA-mimetic; selectively interacts with β2- and β3-subunit containing GABAA receptors
2867 Flupirtine maleate
GABAA modulator; also indirect NMDA antagonist and Kv7 channel activator
2531 Ganaxolone
Potent positive allosteric modulator of GABAA receptors
1295 Loreclezole hydrochloride
Subtype-selective GABAA modulator
4949 MaxiPost
Negative modulator of GABAA receptors; also potassium channel modulator
4410 Ocinaplon
GABAA modulator; anxiolytic
2738 Org 20599
Positive allosteric modulator of GABAA receptors; direct agonist at higher concentrations
2681 17-PA
Antagonist of neurosteroid potentiation and direct gating of GABAA
3652 Pregnanolone
Postitive allosteric modulator of GABAA receptors
5376 Pregnenolone sulfate sodium salt
GABAA inhibitor; displays some subunit selectivity; NMDA potentiator; also activates TRPM3 channels
6192 PZ-II-029
α6β3γ2-selective GABAA positive allosteric modulator
1512 SB 205384
GABAA modulator; slows current decay
6334 THDOC
Positive modulator of GABAA receptors; endogenous neurosteroid
3620 Topiramate
Positive allosteric modulator of GABAA receptors; GluK1 antagonist; also inhibits carbonic anhydrase (CA) II and IV
1558 Tracazolate hydrochloride
Allosteric modulator of GABAA receptors
2734 U 89843A
Positive allosteric modulator of GABAA receptors
2733 U 90042
GABAA ligand
3048 Valerenic acid
Positive allosteric modulator of GABAA receptors

GABAA Receptor Subunits

The majority of human endogenous GABAA receptors are composed of α1-, β2- and γ2-subunits in a 2:2:1 ratio (α2β2γ), however the exact subunit conformation is determined by the expression of different subunits in a given cell type. Some subunits are only expressed in specific brain areas, for example receptors containing the α2-subunit are found in regions where the α1-subunit is absent or expressed at low levels, such as the hippocampus and olfactory bulb. Similarly, the α3-subunit is found in the lateral septum and specific nuclei of the brainstem and thalamus, and the α6-subunit is almost exclusively expressed in the cerebellum. GABAA subunit conformation can also be different at different locations on the same neuron, a process that is mediated by membrane anchoring proteins.

GABAA Receptor Pharmacology

As a results of the heterogeneity of GABAA receptor subunits, and also the presence of multiple binding sites for different compound classes, the pharmacological properties of individual GABAA receptors are very complex. In general, ligands that contribute to or potentiate receptor activation have anticonvulsant, sedative, hypnotic and muscle relaxant effects. In contrast, ligands that decrease receptor activation have the opposite effect; they are convulsant and anxiogenic and may also have nootropic effects.

Depending on the subunit conformation of a GABAA receptor all or a selection of the following pharmacological binding sites may be present.

The GABA binding site of GABAA receptors is located at the interface of α- and β-subunits. The specific α- and β-subunit subtypes in a receptor modulate the efficacy of GABA and competitive ligands at this binding site.

The benzodiazepine binding site is located at the interface of α- and γ-subunits and as such, GABAA receptors that lack a γ-subunit are insensitive to benzodiazepines. Binding of benzodiazepines to this site potentiates GABAergic transmission by locking the receptor into a state that increases its affinity for GABA. This potentiates the inhibitory effect of GABA binding by increasing the frequency of channel opening and therefore hyperpolarization of the synaptic membrane. Some benzodiazepines show selectivity for specific α-subunits and have differing pharmacological profiles. For example, α1- and α5-subunit selective benzodiazepines are associated with sedation and amnesia, whereas α2- and α3-subunit selective benzodiazepines, such as TCS 1105 (Cat. No. 3942) are associated with anxiolytic effects. α4- and α6 subunits generally have a low affinity for classical benzodiazepines, particularly in the presence of a δ-subunit.

The picrotoxin binding site of GABAA receptors is location within the ion pore. Compounds that bind here, such as picrotoxin (Cat. No. 1128) have an antagonistic effect on GABAergic transmission as they physically occlude the ion pore and prevent the passage of Cl- into the cell. They are often described as non-competitive channel blockers.

There are also multiple other allosteric ligand binding sites on GABAA receptors, where ligands that bind have a modulatory effect on GABAergic transmission. For example, ethanol binds with high affinity to δ-subunits and with low affinity to an allosteric transmembrane binding site on α-subunits. Similarly, neurosteroids such as THDOC (Cat. No. 6334) promote channel opening of GABAA receptors that contain the δ-subunit. Barbiturates, such as primidone (Cat. No. 0830), also bind to multiple allosteric transmembrane binding sites, and binding increases the duration of ion channel opening in response to GABA binding. The actions of benzodiazepines, barbiturates and ethanol at GABAA receptors is synergistic, resulting in a high chance of overdose if drug interactions are not carefully controlled.

External sources of pharmacological information for GABAA Receptors :

Literature for GABAA Receptors

Tocris offers the following scientific literature for GABAA Receptors to showcase our products. We invite you to request* your copy today!

*Please note that Tocris will only send literature to established scientific business / institute addresses.


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GABAA Receptor Gene Data

Gene Species Gene Symbol Gene Accession No. Protein Accession No.
GABAA α1 Human GABRA1 NM_001127645 P14867
Mouse Gabra1 NM_010250 P62812
Rat Gabra1 NM_183326 P62813
GABAA α2 Human GABRA2 NM_000807 P47869
Mouse Gabra2 NM_008066 P26048
Rat Gabra2 L08491 P23576
GABAA α3 Human GABRA3 NM_000808 P34903
Mouse Gabra3 NM_008067 P26049
Rat Gabra3 NM_017069 P20236
GABAA α4 Human GABRA4 NM_000809 P48169
Mouse Gabra4 NM_010251 Q9D6F4
Rat Gabra4 NM_080587 P28471
GABAA α5 Human GABRA5 XM_001123369 P31644
Mouse Gabra5 NM_176942 Q8BHJ7
Rat Gabra5 NM_017295 P19969
GABAA α6 Human GABRA6 NM_000811 Q16445
Mouse Gabra6 NM_001099641 P16305
Rat Gabra6 NM_021841 P30191
GABAA β1 Human GABRB1 NM_000812 P18505
Mouse Gabrb1 NM_008069 P50571
Rat Gabrb1 NM_012956 P15431
GABAA β2 Human GABRB2 NM_021911 P47870
Mouse Gabrb2 NM_008070 P63137
Rat Gabrb2 NM_012957 P63138
GABAA β3 Human GABRb3 NM_000814 P28472
Mouse Gabrb3 NM_008071 P63080
Rat Gabrb3 NM_017065 P63079
GABAA γ1 Human GABRG1 NM_173536 Q8N1C3
Mouse Gabrg1 NM_010252 Q9R0Y8
Rat Gabrg1 NM_080586 P23574
GABAA γ2 Human GABRG2 NM_198903 P18507
Mouse Gabrg2 NM_177408 P22723
Rat Gabrg2 NM_183327 P18508
GABAA γ3 Human GABRG3 NM_033223 Q99928
Mouse Gabrg3 NM_008074 P27681
Rat Gabrg3 NM_024370 P28473
GABAA δ Human GABRD NM_000815 O14764
Mouse Gabrd NM_008072 P22933
Rat Gabrd NM_017289 P18506
GABAA ε Human GABRE NM_004961 P78334
Mouse Gabre NM_017369 NP_059065
Rat Gabre NM_023091 Q9ES14
GABAA π Human GABRP NM_014211 O00591
Mouse Gabrp NM_146017 Q8QZW7
Rat Gabrp NM_031029 O09028
GABAA θ Human GABRQ NM_018558 Q9UN88
Mouse Gabrq NM_020488 Q9JLF1
Rat Gabrq NM_031733 O09028