Human GABAergic transmission through ionotropic GABA-A receptors

Fast GABAergic inhibition in the vertebrate nervous system. GAD1/GAD2 decarboxylate glutamate to GABA in the cytosol of the GABAergic terminal, VGAT (SLC32A1) loads GABA into synaptic vesicles, and calcium-triggered exocytosis releases it. Released GABA opens pentameric GABA-A receptors, which are GABA-gated chloride channels. Two receptor classes are modelled as alternatives. Synaptic gamma2-containing receptors, with (alpha1)2(beta2)2gamma2 as the most abundant example, mediate phasic inhibitory postsynaptic currents. Extrasynaptic delta-containing alpha4/alpha6 receptors respond to ambient GABA and mediate tonic inhibition. The retinal rho1 homopentamer (formerly "GABA-C") is an optional comparator. The plasma-membrane GABA transporter GAT-1 (SLC6A1) terminates the signal by sodium- and chloride-coupled reuptake. Metabotropic GABA-B signalling, GABA catabolism and gephyrin-dependent receptor clustering are outside this module.

MODULE:gabaergic_transmissionDRAFTCONCRETEBiological Processmodules/gabaergic_transmission.yaml
synaptic transmission, GABAergicGO:0051932
PMID:18790874
International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update.
The IUPHAR classification sets the module's reception boundary, covering both the phasic synaptic and the tonic extrasynaptic modes of GABA-A receptor signalling.
GABAA-Rs are chloride channels that are gated by GABA and mediate rapid phasic inhibitory synaptic transmission and also tonic inhibition by producing current in extrasynaptic and perisynaptic locations
PMID:2069816
Two genes encode distinct glutamate decarboxylases.
The two vertebrate GAD isoforms supply the transmitter. The synthesis step is included by reference to the GABA shunt module.
The brain contains two forms of the GABA synthetic enzyme glutamate decarboxylase (GAD)
file:interpro/panther/PTHR18945/PTHR18945-review.yaml
PTHR18945 family review
The family review shows that GABA-gated chloride channel terms in PAINT belong to the GABA-A clades (PTN008360627, PTN008566841), not to the whole neurotransmitter-gated ion channel family. This module therefore names exact subunits and does not use a family-wide selector.

The GABA-A receptor is modelled as specific assembled pentamers, each a complete channel; the subunits are not interchangeable. Native stoichiometry is established only for the abundant (alpha1)2(beta2)2gamma2 receptor; the 2alpha-2beta-1gamma2 arrangement of other gamma2 receptors is assumed by analogy, and the delta receptors are given composition without stoichiometry. VGAT loading and exocytosis are included by module_ref and shared with glycinergic transmission. GAT-3 (SLC6A11) astrocytic uptake is a recognised second clearance route but is not yet grounded here. GABRA1 and GABRB2 now have gene reviews, and both assert contributes_to GABA-gated chloride ion channel activity (GO:0022851) within the GABA-A receptor complex (GO:1902711), which is exactly how this module places the activity: on the assembled pentamer, with the subunits as its active units. The other subunits, VGAT and GAT-1 have no gene review here, so those assertions still rest on the cited literature and PAINT, and status stays DRAFT. Module deep research has not been run.

11Nodes
5Parts
2Variant Sets
5Variants
5Annotons
0Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:gabaergic_transmission deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

0 gene-function check(s) reflected in core functions · 0 conflict(s) · 2 evidence or coverage gap(s) (6 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
gaba_a_a1b2g2_channel PROTEIN_COMPLEX
Gene 		GABA-gated chloride ion channel activity
GO:0022851 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
gaba_a_a4b2d_channel PROTEIN_COMPLEX
Gene 		GABA-gated chloride ion channel activity
GO:0022851 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
gaba_a_a6b2d_channel PROTEIN_COMPLEX
Gene 		GABA-gated chloride ion channel activity
GO:0022851 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
gaba_a_rho1_channel PROTEIN_COMPLEX
Gene 		GABA-gated chloride ion channel activity
GO:0022851 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
slc6a1_gaba_uptake SLC6A1 (GAT-1)
UniProtKB:P30531
Gene 		gamma-aminobutyric acid:sodium:chloride symporter activity
GO:0005332 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
slc6a1_gaba_uptake GAT-1 subfamily of SLC6 sodium/chloride-dependent transporters
PANTHER:PTHR11616:SF138
Family 		gamma-aminobutyric acid:sodium:chloride symporter activity
GO:0005332 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR11616:SF138.

Gene-review completeness (3/8 grounded genes reviewed)

0 complete review(s) · 0 with deep research · 5 missing review · 3 reviewed but lacking deep research

Gene Review Complete Deep research
GABRA1 P14867 ✓ 63/66 ✗
GABRB2 P47870 ✓ 63/66 ✗
GABRG2 P18507 ✓ 73/74 ✗
GABRD O14764 ✗ — —
GABRR1 P24046 ✗ — —
SLC6A1 (GAT-1) P30531 ✗ — —
GABRA4 P48169 ✗ — —
GABRA6 Q16445 ✗ — —

Details

Context
Homo sapiensNCBITaxon:9606
GABA-ergic synapseGO:0098982
GABAergic transmission via GABA-A receptorsBiological Processgabaergic_transmission
synaptic transmission, GABAergicGO:0051932
Context
Homo sapiensNCBITaxon:9606
GABA-ergic synapseGO:0098982
Part 1: GABA synthesis
GAD1/GAD2 decarboxylation of glutamate to GABAgaba_synthesis

Included by reference to the animal glutamate decarboxylase variant of the GABA shunt module.

Realized by module gaba_shunt#animal_gad

Part 2: vesicular GABA loading
VGAT (SLC32A1) loading of GABA into synaptic vesiclesgaba_vesicle_loading

Included by reference to the VGAT variant of the synaptic vesicle neurotransmitter-loading module.

Realized by module synaptic_vesicle_neurotransmitter_loading#gaba_glycine_loading

PMID:9349821
Identification and characterization of the vesicular GABA transporter.
Identification of VGAT as the vesicular GABA transporter (rat homologue of C. elegans UNC-47).
a rat homologue of unc-47 is expressed by central GABA neurons and confers vesicular GABA transport in transfected cells
Part 3: calcium-triggered vesicular GABA release
Synaptic vesicle exocytosis of GABAgaba_release

Included by reference to the transmitter-agnostic synaptic vesicle exocytosis module.

Realized by module synaptic_vesicle_exocytosis

Part 4: GABA reception
GABA-A receptor chloride-channel activationSignaling Pathwaygaba_a_reception

GABA binds at beta(+)/alpha(-) interfaces and opens the integral chloride pore. Each alternative below is a complete assembled receptor.

Variant set: GABA-A receptor class by subunit composition / synaptic versus extrasynaptic location [Realizer] (One Or More)

Many neurons express both classes, so phasic and tonic inhibition coexist.

Synaptic (alpha1)2(beta2)2gamma2 GABA-A receptorProtein Complexgaba_a_synaptic_a1b2g2

The most abundant GABA-A receptor in the brain. The gamma2 subunit is required for synaptic localisation.

Context
Homo sapiensNCBITaxon:9606

Annotons

(alpha1)2(beta2)2gamma2 GABA-gated chloride channel
gaba_a_a1b2g2_channel
Participant: Protein Complex: (alpha1)2(beta2)2gamma2 GABA-A receptor
Protein Complex:
(alpha1)2(beta2)2gamma2 GABA-A receptorGO:1902711
Active units:
alpha1 subunit (two copies)2
Participant: Gene Product: GABRA1
Gene Product:
GABRA1UniProtKB:P14867
Family:
GABA-A receptor alpha-1 subfamilyPANTHER:PTHR18945:SF514 Classification of the named subunit. The PANTHER family also contains cation-selective and other anion-selective channels, so GABA gating is not asserted for the whole family.
Representative Members: GABRA1UniProtKB:P14867
Role: Complementary (-) face of both GABA sites; principal face of the benzodiazepine site with gamma2.
beta2 subunit (two copies)2
Participant: Gene Product: GABRB2
Gene Product:
GABRB2UniProtKB:P47870
Family:
GABA-A receptor beta-2 subfamilyPANTHER:PTHR18945:SF221 Classification of the named subunit. GABA gating is not asserted for the whole PANTHER family.
Representative Members: GABRB2UniProtKB:P47870
Role: Principal (+) face of both GABA sites.
gamma2 subunit1
Participant: Gene Product: GABRG2
Gene Product:
GABRG2UniProtKB:P18507
Family:
GABA-A receptor gamma-2 subfamilyPANTHER:PTHR18945:SF498 Classification of the named subunit. GABA gating is not asserted for the whole PANTHER family.
Representative Members: GABRG2UniProtKB:P18507
Role: Fifth subunit; required for synaptic localisation and benzodiazepine sensitivity.

Function

GABA-gated chloride ion channel activityGO:0022851
Substrates: GABA (agonist)CHEBI:16865

Processes

synaptic transmission, GABAergicGO:0051932

Locations

postsynaptic specialization membraneGO:0099634

Mediates phasic inhibitory postsynaptic currents at GABAergic synapses.

PMID:18790874
Evidence for the (alpha1)2(beta2)2gamma2 stoichiometry and abundance.
some evidence for the likely subunit combination and stoichiometry of the abundant (α1)2(β2)2γ2 heteropentameric subtypes
PMID:18790874
Alpha1 is the most abundant alpha subunit and co-occurs with beta2 and gamma2.
The α1 is the most abundant of the α subunits and is often colocalized with its chromosome partners, the likewise highly expressed β2 and γ2 subunits
PMID:18790874
The gamma2 subunit is what targets these receptors to synapses.
The γ2 subunit is required for synaptic localization of GABAA-Rs, usually associated with the α1, α2, or α3 subunits.
Extrasynaptic delta-containing GABA-A receptorsSignaling Pathwaygaba_a_extrasynaptic_delta

High-affinity, slowly desensitising alpha4/alpha6-beta-delta receptors outside the synapse that respond to ambient GABA and carry tonic inhibitory current. Alpha4 receptors are forebrain (e.g. dentate gyrus, thalamus); alpha6 receptors are cerebellar granule cell receptors.

Variant set: Delta-receptor alpha partner by alpha subunit / brain region [Realizer] (One Or More)
alpha4beta2delta GABA-A receptorProtein Complexgaba_a_a4b2d
Context
Homo sapiensNCBITaxon:9606

Annotons

alpha4beta2delta tonic GABA-gated chloride channel
gaba_a_a4b2d_channel
Participant: Protein Complex: alpha4beta2delta GABA-A receptor
Protein Complex:
alpha4beta2delta GABA-A receptorGO:1902711
Active units:
alpha4 subunit
Participant: Gene Product: GABRA4
Gene Product:
GABRA4UniProtKB:P48169
beta2 subunit
Participant: Gene Product: GABRB2
Gene Product:
GABRB2UniProtKB:P47870
delta subunit
Participant: Gene Product: GABRD
Gene Product:
GABRDUniProtKB:O14764
Role: Replaces gamma2; confers extrasynaptic location and high GABA affinity.

Function

GABA-gated chloride ion channel activityGO:0022851

Processes

extrasynaptic signaling via GABAGO:0160001

Locations

plasma membraneGO:0005886
PMID:18790874
IUPHAR lists alpha4beta2delta among the conclusively identified native subtypes.
we add α4β2δ and α4β3δ, α6β2δ and α6β3δ subtypes in category A
PMID:33834705
Extrasynaptic δ-subunit containing GABA(A) receptors.
Delta receptors are extrasynaptic and carry tonic inhibition.
δ-GABAARs mediate a slow constant inhibitory current called tonic inhibition.
alpha6beta2delta GABA-A receptorProtein Complexgaba_a_a6b2d
Context
Homo sapiensNCBITaxon:9606

Annotons

alpha6beta2delta tonic GABA-gated chloride channel
gaba_a_a6b2d_channel
Participant: Protein Complex: alpha6beta2delta GABA-A receptor
Protein Complex:
alpha6beta2delta GABA-A receptorGO:1902711
Active units:
alpha6 subunit
Participant: Gene Product: GABRA6
Gene Product:
GABRA6UniProtKB:Q16445
beta2 subunit
Participant: Gene Product: GABRB2
Gene Product:
GABRB2UniProtKB:P47870
delta subunit
Participant: Gene Product: GABRD
Gene Product:
GABRDUniProtKB:O14764

Function

GABA-gated chloride ion channel activityGO:0022851

Processes

extrasynaptic signaling via GABAGO:0160001

Locations

plasma membraneGO:0005886
PMID:18790874
IUPHAR lists alpha6beta2delta among the conclusively identified native subtypes.
we add α4β2δ and α4β3δ, α6β2δ and α6β3δ subtypes in category A
Retinal rho1 homopentameric GABA-A receptor (optional comparator)Protein Complexgaba_a_rho1_retina

The former "GABA-C" receptor. It is insensitive to bicuculline and benzodiazepines and is expressed mainly in retina. IUPHAR classifies it as a GABA-A receptor.

Context
Homo sapiensNCBITaxon:9606

Annotons

rho1 GABA-gated chloride channel
gaba_a_rho1_channel
Participant: Protein Complex: rho1 homopentamer
Protein Complex:
rho1 homopentamerGO:1902711
Active units:
rho1 subunit (five copies)5
Participant: Gene Product: GABRR1
Gene Product:
GABRR1UniProtKB:P24046

Function

GABA-gated chloride ion channel activityGO:0022851

Processes

synaptic transmission, GABAergicGO:0051932
PMID:18790874
IUPHAR folds rho subunits into the GABA-A receptor family and does not recommend a separate GABA-C class.
the ρ subunits are closely related in sequence, structure, and function to the other GABAA-R subunit families designated with other Greek letters and thus qualify for inclusion within that family
PMID:18790874
Retinal expression of the rho subunits.
The ρ subunits are all expressed primarily in the retina
Part 5: GABA clearance by neuronal reuptake
GAT-1 (SLC6A1) sodium- and chloride-coupled GABA reuptakeTransport Stepgaba_reuptake

GAT-1, the most abundant GABA transporter, removes GABA from the synaptic cleft and extracellular space and so shapes both phasic and tonic inhibition.

Context
Homo sapiensNCBITaxon:9606

Annotons

GAT-1 GABA:sodium:chloride symport
slc6a1_gaba_uptake
Participant: Gene Product: SLC6A1 (GAT-1)
Gene Product:
SLC6A1 (GAT-1)UniProtKB:P30531
Family:
GAT-1 subfamily of SLC6 sodium/chloride-dependent transportersPANTHER:PTHR11616:SF138 Classification of the named member only; no family-wide GABA transport is asserted for PTHR11616.
Representative Members: SLC6A1 (GAT-1)UniProtKB:P30531

Function

gamma-aminobutyric acid:sodium:chloride symporter activityGO:0005332
Substrates: extracellular GABACHEBI:16865

Processes

gamma-aminobutyric acid reuptakeGO:0051936

Locations

presynaptic membraneGO:0042734

Terminates GABA signalling and limits spillover onto extrasynaptic receptors.

PMID:18248614
GAT-1 regulates both tonic and phasic GABA(A) receptor-mediated inhibition in the cerebral cortex.
GAT-1 knockout cortex shows increased tonic conductance and prolonged evoked IPSCs.
GAT-1 has a prominent role in both tonic and phasic GABA(A)R-mediated inhibition
PMID:18248614
GAT-1 regulates both tonic and phasic GABA(A) receptor-mediated inhibition in the cerebral cortex.
GAT-1 is the dominant GABA transporter.
is the most copiously expressed GABA transporter