Human glycinergic transmission through strychnine-sensitive glycine receptors

Fast glycinergic inhibition, mainly in the spinal cord and brainstem. Glycine is loaded into synaptic vesicles by VGAT (SLC32A1), the same vesicular carrier used for GABA, and released by calcium-triggered exocytosis. Released glycine opens pentameric glycine receptors (GlyRs), which are glycine-gated chloride channels. Adult synaptic receptors contain alpha1 and beta subunits; the beta subunit binds gephyrin and anchors the receptor at the postsynaptic density. Homomeric alpha2 receptors predominate before the postnatal switch to alpha1beta. Two sodium- and chloride-coupled transporters clear glycine. Presynaptic GlyT2 (SLC6A5) recaptures glycine into the terminal and is needed to refill vesicles. Glial GlyT1 (SLC6A9) sets glycine concentrations at the synapse. Glycine's separate role as an NMDA-receptor co-agonist is outside this module, as are gephyrin scaffold assembly and glycine biosynthesis.

MODULE:glycinergic_transmissionDRAFTCONCRETEBiological Processmodules/glycinergic_transmission.yaml
synaptic transmission, glycinergicGO:0060012
PMID:15383648
Molecular structure and function of the glycine receptor chloride channel.
Sets the reception boundary, the subunit inventory and the developmental switch.
The GlyR is best known for mediating inhibitory neurotransmission in the spinal cord and brain stem
PMID:16701208
A shared vesicular carrier allows synaptic corelease of GABA and glycine.
Glycinergic neurons use VGAT, so vesicular loading is shared with the GABAergic module.
glycinergic neurons do not express a separate vesicular glycine transporter
file:interpro/panther/PTHR18945/PTHR18945-review.yaml
PTHR18945 family review
In PAINT, glycine-gated chloride channel activity and glycinergic synapse are asserted only at the glycine receptor node PTN001055255. The wider anion-channel node PTN001055382 also carries invertebrate glutamate-, histamine- and acetylcholine-gated chloride channels. Exact subunits are therefore named here.

GlyR stoichiometry is not asserted: the alpha1beta receptor has been reported both as 2alpha:3beta and as 3alpha:2beta (or 4alpha:1beta). The alpha2 homomer is a developmental alternative, not a required part of the adult synapse. Alpha3-containing receptors of the spinal dorsal horn are not yet modelled. GlyT2 is placed under clearance because it removes glycine from the cleft; its role in supplying glycine for vesicle refilling is recorded on the annoton. No GlyR subunit, VGAT, GlyT1 or GlyT2 has a gene review in this repository, so status is DRAFT. Module deep research has not been run.

7Nodes
4Parts
1Variant Sets
2Variants
4Annotons
0Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:glycinergic_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) · 4 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
glyr_a1b_channel PROTEIN_COMPLEX
Gene 		extracellularly glycine-gated chloride channel activity
GO:0016934 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
glyr_a2_channel PROTEIN_COMPLEX
Gene 		extracellularly glycine-gated chloride channel activity
GO:0016934 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
slc6a5_glycine_uptake SLC6A5 (GlyT2)
UniProtKB:Q9Y345
Gene 		glycine:sodium symporter activity
GO:0015375 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
slc6a9_glycine_uptake SLC6A9 (GlyT1)
UniProtKB:P48067
Gene 		glycine:sodium symporter activity
GO:0015375 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
slc6a5_glycine_uptake GlyT2 subfamily of SLC6 sodium/chloride-dependent transporters
PANTHER:PTHR11616:SF241
Family 		glycine:sodium symporter activity
GO:0015375 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR11616:SF241.
slc6a9_glycine_uptake GlyT1 subfamily of SLC6 sodium/chloride-dependent transporters
PANTHER:PTHR11616:SF263
Family 		glycine:sodium symporter activity
GO:0015375 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR11616:SF263.

Gene-review completeness (0/5 grounded genes reviewed)

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

Gene Review Complete Deep research
GLRA1 P23415 ✗ — —
GLRA2 P23416 ✗ — —
SLC6A9 (GlyT1) P48067 ✗ — —
GLRB P48167 ✗ — —
SLC6A5 (GlyT2) Q9Y345 ✗ — —

Details

Context
Homo sapiensNCBITaxon:9606
glycinergic synapseGO:0098690
Glycinergic transmission via glycine receptorsBiological Processglycinergic_transmission
synaptic transmission, glycinergicGO:0060012
Context
Homo sapiensNCBITaxon:9606
glycinergic synapseGO:0098690
Part 1: vesicular glycine loading
VGAT (SLC32A1) loading of glycine into synaptic vesiclesglycine_vesicle_loading

Included by reference to the VGAT variant of the synaptic vesicle neurotransmitter-loading module, the same step used by GABAergic terminals.

Realized by module synaptic_vesicle_neurotransmitter_loading#gaba_glycine_loading

PMID:16701208
A shared vesicular carrier allows synaptic corelease of GABA and glycine.
VGAT knockout abolishes most release from both GABAergic and glycinergic neurons.
Loss of Viaat causes a drastic reduction of neurotransmitter release in both GABAergic and glycinergic neurons
Part 2: calcium-triggered vesicular glycine release
Synaptic vesicle exocytosis of glycineglycine_release

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

Realized by module synaptic_vesicle_exocytosis

Part 3: glycine reception
Glycine receptor chloride-channel activationSignaling Pathwayglycine_reception

Glycine binds at subunit interfaces in the extracellular domain and opens the chloride pore. Each alternative is a complete receptor.

Variant set: Glycine receptor subtype by developmental stage / subunit composition [Realizer] (One Or More)

The alpha2-to-alpha1beta switch is completed around postnatal day 20 in rat, and the two forms coexist during the transition.

Adult synaptic alpha1beta glycine receptorProtein Complexglyr_adult_a1b
Context
Homo sapiensNCBITaxon:9606

Annotons

alpha1beta glycine-gated chloride channel
glyr_a1b_channel
Participant: Protein Complex: alpha1beta glycine receptor
Protein Complex:
alpha1beta glycine receptorGO:0016935
Active units:
alpha1 subunit
Participant: Gene Product: GLRA1
Gene Product:
GLRA1UniProtKB:P23415
Family:
Glycine receptor alpha-1 subfamilyPANTHER:PTHR18945:SF213 Classification of the named subunit. The glycine-receptor PAINT node is recorded on the beta subunit below, which is its UniProtKB seed.
Representative Members: GLRA1UniProtKB:P23415
Role: Carries the principal face of the glycine and strychnine binding sites.
beta subunit
Participant: Gene Product: GLRB
Gene Product:
GLRBUniProtKB:P48167
Family:
Glycine receptor beta subfamilyPANTHER:PTHR18945:SF29 Classification of the named subunit. Glycine gating is not asserted for the whole PANTHER family, which also holds cation-selective channels.
Representative Members: GLRBUniProtKB:P48167
Role: Structural subunit. Its large intracellular M3-M4 loop binds gephyrin and anchors the receptor at the synapse.

Function

extracellularly glycine-gated chloride channel activityGO:0016934
Substrates: glycine (agonist)CHEBI:15428

Processes

synaptic transmission, glycinergicGO:0060012

Locations

postsynaptic specialization membraneGO:0099634

The principal adult inhibitory glycine receptor of spinal cord and brainstem.

PMID:15383648
The developmental switch establishes alpha1beta as the adult receptor.
A developmental switch from alpha2 to alpha1beta is completed by around postnatal day 20 in the rat.
PMID:15383648
The beta subunit anchors the receptor through gephyrin.
The beta-subunit is responsible for anchoring GlyRs to the subsynaptic cytoskeleton via the cytoplasmic protein gephyrin.
PMID:7546736
Identification of a gephyrin binding motif on the glycine receptor beta subunit.
The gephyrin-binding site lies in the beta-subunit M3-M4 loop; alpha subunits do not bind gephyrin.
identified a gephyrin binding site in the cytoplasmic loop between the third and fourth transmembrane segments of the beta subunit
Neonatal alpha2 homomeric glycine receptorProtein Complexglyr_neonatal_a2

The predominant embryonic and neonatal receptor. It lacks the beta subunit, so it is not anchored by gephyrin. In immature neurons with high intracellular chloride, its opening can depolarise the cell.

Context
Homo sapiensNCBITaxon:9606

Annotons

alpha2 homomeric glycine-gated chloride channel
glyr_a2_channel
Participant: Protein Complex: alpha2 homopentamer
Protein Complex:
alpha2 homopentamerGO:0016935
Active units:
alpha2 subunit (five copies)5
Participant: Gene Product: GLRA2
Gene Product:
GLRA2UniProtKB:P23416

Function

extracellularly glycine-gated chloride channel activityGO:0016934

Locations

plasma membraneGO:0005886
PMID:15383648
GlyRs, notably in embryonic neurons, can also mediate excitation.
including excitatory neurotransmission in embryonic neurons
Part 4: glycine clearance by presynaptic and glial transporters
Sodium- and chloride-coupled glycine uptakeTransport Stepglycine_clearance

Two SLC6 transporters remove glycine from the extracellular space. Both are required in vivo, and their knockouts give opposite phenotypes, so they are modelled as parts rather than alternatives.

Context
Homo sapiensNCBITaxon:9606

Annotons

GlyT2 (SLC6A5) presynaptic glycine:sodium symport
slc6a5_glycine_uptake
Participant: Gene Product: SLC6A5 (GlyT2)
Gene Product:
SLC6A5 (GlyT2)UniProtKB:Q9Y345
Family:
GlyT2 subfamily of SLC6 sodium/chloride-dependent transportersPANTHER:PTHR11616:SF241 Classification of the named member only; no family-wide glycine transport is asserted for PTHR11616.
Representative Members: SLC6A5 (GlyT2)UniProtKB:Q9Y345

Function

glycine:sodium symporter activityGO:0015375
Substrates: extracellular glycineCHEBI:15428

Processes

glycine import across plasma membraneGO:1903804

Locations

presynaptic membraneGO:0042734

Recaptures released glycine into the glycinergic terminal. Beyond clearance, this uptake supplies the cytosolic glycine that VGAT loads into vesicles, so loss of GlyT2 reduces the glycine content of vesicles rather than the number of receptors.

PMID:14622583
Deletion of the mouse glycine transporter 2 results in a hyperekplexia phenotype and postnatal lethality.
GlyT2 is presynaptic, and its loss reduces glycinergic miniature current amplitudes, which indicates failure of vesicle filling rather than loss of receptors.
postnatal GlyT2 function is crucial for efficient transmitter loading of synaptic vesicles in glycinergic nerve terminals
PMID:14622583
Deletion of the mouse glycine transporter 2 results in a hyperekplexia phenotype and postnatal lethality.
Localisation of GlyT2 to glycinergic axon terminals.
The glycine transporter subtype 2 (GlyT2) is localized in the axon terminals of glycinergic neurons.
GlyT1 (SLC6A9) glial glycine:sodium symport
slc6a9_glycine_uptake
Participant: Gene Product: SLC6A9 (GlyT1)
Gene Product:
SLC6A9 (GlyT1)UniProtKB:P48067
Family:
GlyT1 subfamily of SLC6 sodium/chloride-dependent transportersPANTHER:PTHR11616:SF263 Classification of the named member only; no family-wide glycine transport is asserted for PTHR11616.
Representative Members: SLC6A9 (GlyT1)UniProtKB:P48067

Function

glycine:sodium symporter activityGO:0015375
Substrates: extracellular glycineCHEBI:15428

Processes

glycine import across plasma membraneGO:1903804

Locations

plasma membraneGO:0005886

Astroglial uptake that keeps glycine at inhibitory receptors low. Its loss causes excess glycinergic inhibition that strychnine reverses, which is the opposite direction from GlyT2 loss.

PMID:14622582
Inactivation of the glycine transporter 1 gene discloses vital role of glial glycine uptake in glycinergic inhibition.
GlyT1 sets glycine concentrations at inhibitory glycine receptors; its loss is lethal and the phenotype is reversed by a glycine receptor antagonist.
during early postnatal life, GlyT1 is essential for regulating glycine concentrations at inhibitory GlyRs
PMID:14622582
Inactivation of the glycine transporter 1 gene discloses vital role of glial glycine uptake in glycinergic inhibition.
GlyT1 is expressed in astroglia.
The glycine transporter subtype 1 (GlyT1) is widely expressed in astroglial cells