Human serotonergic signalling through ionotropic 5-HT3 receptors

The ionotropic arm of serotonergic transmission. Serotonin is synthesised from tryptophan by TPH2 and DDC, loaded into vesicles by VMAT2 (SLC18A2) and released by calcium-triggered exocytosis. Released serotonin opens 5-HT3 receptors, the only pentameric ligand-gated channels among the serotonin receptors; the other 5-HT receptor classes are G-protein-coupled and are outside this module. Two receptor forms are modelled as alternatives: the 5-HT3A homopentamer, which is calcium-permeable but has a conductance too small to resolve directly, and the 5-HT3A/5-HT3B heteromer, which has a large single-channel conductance and low calcium permeability. The signal is terminated by SERT (SLC6A4), which recaptures serotonin into the presynaptic terminal. Melatonin synthesis, monoamine oxidase degradation and the metabotropic 5-HT receptors are outside this module.

MODULE:serotonergic_5ht3_signalingDRAFTCONCRETEBiological Processmodules/serotonergic_5ht3_signaling.yaml
synaptic transmission, serotonergicGO:0099153 serotonin-gated cation-selective signaling pathwayGO:0140227
PMID:9950429
The 5-HT3B subunit is a major determinant of serotonin-receptor function.
Establishes the two receptor forms used as the variant axis, and the functional differences between them.
Heteromeric assemblies of 5-HT3A and 5-HT3B subunits display a large single-channel conductance (16 pS), low permeability to calcium ions, and a current-voltage relationship which resembles that of characterized neuronal 5-HT3 channels.
PMID:25119048
X-ray structure of the mouse serotonin 5-HT3 receptor.
The 5-HT3 receptor is a Cys-loop pentamer with an extracellular agonist site and an aqueous transmembrane pore, which is the architecture asserted here.
The extracellular domain reveals the detailed anatomy of the neurotransmitter binding site capped by a nanobody. The membrane domain delimits an aqueous pore with a 4.6 Å constriction.
file:interpro/panther/PTHR18945/PTHR18945-review.yaml
PTHR18945 family review
The family review finds the serotonin-gated activity gain placed too deep in PAINT, at PTN004502671, where three IRDs then cancel it for the alpha9, alpha10 and ZAC branches. The 5-HT3 nodes carry the serotonin-activated channel complex gains. This module therefore names exact subunits and takes its receptor claims from the structural and electrophysiological literature rather than from the family-level propagation.

The subunit stoichiometry of the 5-HT3A/5-HT3B heteromer is not asserted; the paper that identified 5-HT3B did not fix it, and later reports disagree. The homomer is given five copies of 5-HT3A, which the structural work supports. HTR3C, HTR3D and HTR3E exist and inherit the serotonin-activated channel complex term at PAINT node PTN002707828, but their native assemblies are not established, so they are not modelled. TPH1 is the peripheral isoform; the biosynthesis reference covers both. Synthesis, vesicular loading and exocytosis are included by module_ref. No 5-HT3 subunit, VMAT2 or SERT has a gene review in this repository, although TPH2 and DDC do, so status is DRAFT. Module deep research has not been run.

8Nodes
5Parts
1Variant Sets
2Variants
3Annotons
0Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:serotonergic_5ht3_signaling 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) (4 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
ht3_homomeric_a_channel PROTEIN_COMPLEX
Gene 		serotonin-gated monoatomic cation channel activity
GO:0022850 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
ht3_heteromeric_ab_channel PROTEIN_COMPLEX
Gene 		serotonin-gated monoatomic cation channel activity
GO:0022850 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
slc6a4_serotonin_uptake SLC6A4 (SERT)
UniProtKB:P31645
Gene 		serotonin:sodium:chloride symporter activity
GO:0005335 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
slc6a4_serotonin_uptake SERT subfamily of SLC6 sodium/chloride-dependent transporters
PANTHER:PTHR11616:SF105
Family 		serotonin:sodium:chloride symporter activity
GO:0005335 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR11616:SF105.

Gene-review completeness (0/3 grounded genes reviewed)

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

Gene Review Complete Deep research
HTR3B O95264 ✗ — —
SLC6A4 (SERT) P31645 ✗ — —
HTR3A P46098 ✗ — —

Details

Context
Homo sapiensNCBITaxon:9606
serotonergic synapseGO:0099154
Serotonergic signalling via 5-HT3 receptorsBiological Processserotonergic_5ht3_signaling
synaptic transmission, serotonergicGO:0099153 serotonin-gated cation-selective signaling pathwayGO:0140227
Context
Homo sapiensNCBITaxon:9606
serotonergic synapseGO:0099154
Part 1: serotonin synthesis
TPH2 and DDC synthesis of serotonin from tryptophanserotonin_synthesis

Included by reference to the serotonin and melatonin biosynthesis module, whose first two steps are tryptophan 5-hydroxylation and decarboxylation of 5-hydroxytryptophan.

Realized by module serotonin_melatonin_biosynthesis

PMID:12511643
Synthesis of serotonin by a second tryptophan hydroxylase isoform.
TPH2 is the neuronal tryptophan hydroxylase isoform, which is why the neuronal branch of the biosynthesis module applies here.
Part 2: vesicular serotonin loading
VMAT2 (SLC18A2) loading of serotonin into synaptic vesiclesserotonin_vesicle_loading

Included by reference to the monoamine variant of the synaptic vesicle neurotransmitter-loading module, which models VMAT2 proton-antiport of monoamines.

Realized by module synaptic_vesicle_neurotransmitter_loading#monoamine_loading

PMID:9427251
Knockout of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine.
VMAT2 is the brain monoamine vesicular transporter, and its loss abolishes vesicular monoamine storage and release.
manifesting severely impaired monoamine storage and vesicular release
Part 3: calcium-triggered vesicular serotonin release
Synaptic vesicle exocytosis of serotoninserotonin_release

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

Realized by module synaptic_vesicle_exocytosis

Part 4: serotonin reception by ionotropic receptors
5-HT3 receptor cation-channel activationSignaling Pathwayht3_reception

Serotonin binds the extracellular domain and opens a cation-selective pore, depolarising the target cell. Each alternative is a complete assembled receptor.

Variant set: 5-HT3 receptor subtype by subunit composition [Realizer] (One Or More)

The two forms coexist in brain regions where HTR3B is expressed, so the selection is ONE_OR_MORE rather than EXACTLY_ONE.

5-HT3A homopentameric receptorProtein Complexht3_homomeric_a

The homomer formed by HTR3A alone. It is calcium-permeable, but its single-channel conductance is below the resolution of direct recording, unlike neuronal 5-HT3 channels.

Context
Homo sapiensNCBITaxon:9606

Annotons

5-HT3A serotonin-gated cation channel
ht3_homomeric_a_channel
Participant: Protein Complex: 5-HT3A homopentamer
Protein Complex:
5-HT3A homopentamerGO:1904602
Active units:
5-HT3A subunit (five copies)5
Participant: Gene Product: HTR3A
Gene Product:
HTR3AUniProtKB:P46098
Family:
5-hydroxytryptamine receptor 3A subfamilyPANTHER:PTHR18945:SF52 Classification of the named subunit. Serotonin gating is not asserted for the whole PANTHER family, which also holds acetylcholine-gated and anion-selective channels.
Representative Members: HTR3AUniProtKB:P46098
Role: Carries both faces of the serotonin binding site and lines the pore.

Function

serotonin-gated monoatomic cation channel activityGO:0022850
Substrates: serotonin (agonist)CHEBI:28790

Processes

serotonin-gated cation-selective signaling pathwayGO:0140227

Locations

plasma membraneGO:0005886

The minimal functional 5-HT3 receptor. Recombinant HTR3A alone gives serotonin-gated channels, which is why it is a complete alternative rather than a subunit requiring a partner.

PMID:9950429
HTR3A alone yields functional receptors.
Recombinant expression of the only identified receptor subunit (5-HT3A) yields functional 5-HT3 receptors.
PMID:9950429
The homomer's conductance is unresolvably small and differs from neuronal channels.
the conductance of these homomeric receptors (sub-picosiemens) is too small to be resolved directly
PMID:25119048
The pentameric Cys-loop architecture was determined for the mouse 5-HT3 receptor.
Here we present the X-ray structure of a mammalian Cys-loop receptor, the mouse serotonin 5-HT3 receptor, at 3.5 Å resolution.
5-HT3A/5-HT3B heteromeric receptorProtein Complexht3_heteromeric_ab

The heteromer whose large single-channel conductance and low calcium permeability match native neuronal 5-HT3 channels. HTR3B transcripts are co-expressed with HTR3A in amygdala, caudate and hippocampus.

Context
Homo sapiensNCBITaxon:9606

Annotons

5-HT3A/5-HT3B serotonin-gated cation channel
ht3_heteromeric_ab_channel
Participant: Protein Complex: 5-HT3A/5-HT3B heteromer
Protein Complex:
5-HT3A/5-HT3B heteromerGO:1904602
Active units:
5-HT3A subunit
Participant: Gene Product: HTR3A
Gene Product:
HTR3AUniProtKB:P46098
Role: Supplies the serotonin binding site; required, because HTR3B does not form functional homomers.
5-HT3B subunit
Participant: Gene Product: HTR3B
Gene Product:
HTR3BUniProtKB:O95264
Family:
5-hydroxytryptamine receptor 3B subfamilyPANTHER:PTHR18945:SF53 Classification of the named subunit. Serotonin gating is not asserted for the whole PANTHER family.
Representative Members: HTR3BUniProtKB:O95264
Role: Sets the channel's conductance and calcium permeability, although its M2 region lacks the features known to raise conductance in related receptors.

Function

serotonin-gated monoatomic cation channel activityGO:0022850
Substrates: serotonin (agonist)CHEBI:28790

Processes

serotonin-gated cation-selective signaling pathwayGO:0140227

Locations

plasma membraneGO:0005886

The form whose conductance and calcium permeability match native neuronal 5-HT3 receptors.

PMID:9950429
Heteromer biophysics match native neuronal channels.
Heteromeric assemblies of 5-HT3A and 5-HT3B subunits display a large single-channel conductance (16 pS), low permeability to calcium ions, and a current-voltage relationship which resembles that of characterized neuronal 5-HT3 channels.
PMID:9950429
Co-expression of the two transcripts in specific brain regions.
Transcripts of this subunit are co-expressed with the 5-HT3A subunit in the amygdala, caudate and hippocampus.
PMID:9950429
The conductance effect of 5-HT3B is not explained by its pore sequence, so the mechanism is not asserted here.
the M2 region of the 5-HT3B subunit lacks any of the structural features that are known to promote the conductance of related receptors
Part 5: serotonin clearance by presynaptic reuptake
SERT (SLC6A4) sodium-coupled serotonin reuptakeTransport Stepserotonin_reuptake

SERT recaptures released serotonin into the presynaptic terminal, setting extracellular serotonin concentrations. It is the target of the serotonin reuptake inhibitors.

Context
Homo sapiensNCBITaxon:9606

Annotons

SERT serotonin:sodium:chloride symport
slc6a4_serotonin_uptake
Participant: Gene Product: SLC6A4 (SERT)
Gene Product:
SLC6A4 (SERT)UniProtKB:P31645
Family:
SERT subfamily of SLC6 sodium/chloride-dependent transportersPANTHER:PTHR11616:SF105 Classification of the named member only; no family-wide serotonin transport is asserted for PTHR11616.
Representative Members: SLC6A4 (SERT)UniProtKB:P31645

Function

serotonin:sodium:chloride symporter activityGO:0005335
Substrates: extracellular serotoninCHEBI:28790

Processes

serotonin uptakeGO:0051610

Locations

presynaptic membraneGO:0042734

Terminates serotonergic signalling and so determines how much serotonin reaches 5-HT3 and the metabotropic receptors.

PMID:15087484
Serotonin transporter: gene, genetic disorders, and pharmacogenetics.
SERT sets extracellular serotonin concentrations for the whole serotonergic system and is the target of the SRIs.
The highly evolutionarily conserved serotonin transporter (SERT) regulates the entire serotoninergic system and its receptors via modulation of extracellular fluid serotonin concentrations.