NtR is a membrane protein of the Cys-loop ligand-gated ion-channel family, with an extracellular ligand-binding region and a hydrophobic C-terminal channel region. It occupies a distinct unclassified branch related to nicotinic receptor subunits. A general ligand-gated ion-channel role is supported by conserved architecture and family placement, while its activating ligand, ion selectivity, native partners and physiological signaling context remain unresolved. The protein also contains an N-terminal methyltransferase-like region of unknown biochemical role.
Existing Annotations Review
GO Term
Evidence
Action
Reason
GO:0005230 extracellular ligand-gated monoatomic ion channel activity
IEA GO_REF:0000002
ACCEPT
Summary: NtR is an unclassified Cys-loop ligand-gated channel subunit in the published insect channel-family tree.
Reason: NtR is an unclassified Cys-loop ligand-gated channel subunit in the published insect channel-family tree. Its ligand-binding architecture and membrane-spanning C-terminal region support a plasma-membrane ion-channel role and consequent membrane-potential regulation by conserved family inference. The ligand and ion selectivity remain unresolved.
Supporting Evidence:
file:DROME/NtR/NtR-family-evidence.md
The published Cys-loop ligand-gated ion-channel tree in Matthews et al. (2018), Extended Data Figure 10d, includes Dmel NTR as a distinct branch outside both shaded nicotinic acetylcholine-receptor groups.
Summary: NtR is an unclassified Cys-loop ligand-gated channel subunit in the published insect channel-family tree.
Reason: NtR is an unclassified Cys-loop ligand-gated channel subunit in the published insect channel-family tree. Its ligand-binding architecture and membrane-spanning C-terminal region support a plasma-membrane ion-channel role and consequent membrane-potential regulation by conserved family inference. The ligand and ion selectivity remain unresolved.
Supporting Evidence:
file:DROME/NtR/NtR-family-evidence.md
The published Cys-loop ligand-gated ion-channel tree in Matthews et al. (2018), Extended Data Figure 10d, includes Dmel NTR as a distinct branch outside both shaded nicotinic acetylcholine-receptor groups.
Summary: NtR occupies a distinct unclassified branch in the primary Cys-loop channel tree, outside the explicitly identified core and divergent nicotinic acetylcholine-receptor groups.
Reason: NtR occupies a distinct unclassified branch in the primary Cys-loop channel tree, outside the explicitly identified core and divergent nicotinic acetylcholine-receptor groups. This is target-specific uncertainty about the placement of ligand/selectivity functions on the ancestral lineage: broad channel homology does not resolve acetylcholine gating or calcium permeability for this branch. No target ligand or ion-selectivity assay was found. The specific IBA is neither confirmed nor refuted; broad ligand-gated channel function remains supported. The Falcon report found no direct assay, but its broader skepticism about channel membership is not adopted; the actual uncertainty is the NTR branch-specific functional assignment.
Propagation Review
Root cause:UNRESOLVED
Sources checked:
PANTHER:PTN000435923UNRESOLVED
The descendant-supported ancestral assertion remains under review for the target-specific lineage/functional scope described in the rationale; donor number and target self-inclusion are not objections.
Supporting Evidence:
file:DROME/NtR/NtR-family-evidence.md
The published Cys-loop ligand-gated ion-channel tree in Matthews et al. (2018), Extended Data Figure 10d, includes Dmel NTR as a distinct branch outside both shaded nicotinic acetylcholine-receptor groups.
file:DROME/NtR/NtR-flybase.txt
UNCLASSIFIED LIGAND-GATED ION CHANNEL SUBUNITS
file:DROME/NtR/NtR-deep-research-falcon.md
No ligand-binding or electrophysiological experiment establishes association with a neuronal channel.
Summary: Retain the broad monoatomic ion transport annotation.
Reason: The published Cys-loop channel-family placement, FlyBase channel grouping and membrane-spanning architecture support this broad annotation. The more specific existing channel/transport/location terms do not make their true ancestor incorrect or non-core. Ligand identity and ion selectivity are separate unresolved questions.
Supporting Evidence:
file:DROME/NtR/NtR-family-evidence.md
The published Cys-loop ligand-gated ion-channel tree in Matthews et al. (2018), Extended Data Figure 10d, includes Dmel NTR as a distinct branch outside both shaded nicotinic acetylcholine-receptor groups.
Summary: NtR occupies a distinct unclassified branch in the primary Cys-loop channel tree, outside the explicitly identified core and divergent nicotinic acetylcholine-receptor groups.
Reason: NtR occupies a distinct unclassified branch in the primary Cys-loop channel tree, outside the explicitly identified core and divergent nicotinic acetylcholine-receptor groups. This is target-specific uncertainty about the placement of ligand/selectivity functions on the ancestral lineage: broad channel homology does not resolve acetylcholine gating or calcium permeability for this branch. No target ligand or ion-selectivity assay was found. The specific IBA is neither confirmed nor refuted; broad ligand-gated channel function remains supported. The Falcon report found no direct assay, but its broader skepticism about channel membership is not adopted; the actual uncertainty is the NTR branch-specific functional assignment.
Propagation Review
Root cause:UNRESOLVED
Sources checked:
PANTHER:PTN000434994UNRESOLVED
The descendant-supported ancestral assertion remains under review for the target-specific lineage/functional scope described in the rationale; donor number and target self-inclusion are not objections.
Supporting Evidence:
file:DROME/NtR/NtR-family-evidence.md
The published Cys-loop ligand-gated ion-channel tree in Matthews et al. (2018), Extended Data Figure 10d, includes Dmel NTR as a distinct branch outside both shaded nicotinic acetylcholine-receptor groups.
file:DROME/NtR/NtR-flybase.txt
UNCLASSIFIED LIGAND-GATED ION CHANNEL SUBUNITS
file:DROME/NtR/NtR-deep-research-falcon.md
No ligand-binding or electrophysiological experiment establishes association with a neuronal channel.
Summary: NtR occupies a distinct unclassified branch in the primary Cys-loop channel tree, outside the explicitly identified core and divergent nicotinic acetylcholine-receptor groups.
Reason: NtR occupies a distinct unclassified branch in the primary Cys-loop channel tree, outside the explicitly identified core and divergent nicotinic acetylcholine-receptor groups. This is target-specific uncertainty about the placement of ligand/selectivity functions on the ancestral lineage: broad channel homology does not resolve acetylcholine gating or calcium permeability for this branch. No target ligand or ion-selectivity assay was found. The specific IBA is neither confirmed nor refuted; broad ligand-gated channel function remains supported. The Falcon report found no direct assay, but its broader skepticism about channel membership is not adopted; the actual uncertainty is the NTR branch-specific functional assignment.
Propagation Review
Root cause:UNRESOLVED
Sources checked:
PANTHER:PTN001054960UNRESOLVED
The descendant-supported ancestral assertion remains under review for the target-specific lineage/functional scope described in the rationale; donor number and target self-inclusion are not objections.
Supporting Evidence:
file:DROME/NtR/NtR-family-evidence.md
The published Cys-loop ligand-gated ion-channel tree in Matthews et al. (2018), Extended Data Figure 10d, includes Dmel NTR as a distinct branch outside both shaded nicotinic acetylcholine-receptor groups.
file:DROME/NtR/NtR-flybase.txt
UNCLASSIFIED LIGAND-GATED ION CHANNEL SUBUNITS
file:DROME/NtR/NtR-deep-research-falcon.md
No ligand-binding or electrophysiological experiment establishes association with a neuronal channel.
Reason: The published Cys-loop channel-family placement, FlyBase channel grouping and membrane-spanning architecture support this broad annotation. The more specific existing channel/transport/location terms do not make their true ancestor incorrect or non-core. Ligand identity and ion selectivity are separate unresolved questions.
Supporting Evidence:
file:DROME/NtR/NtR-family-evidence.md
The published Cys-loop ligand-gated ion-channel tree in Matthews et al. (2018), Extended Data Figure 10d, includes Dmel NTR as a distinct branch outside both shaded nicotinic acetylcholine-receptor groups.
Summary: NtR occupies a distinct unclassified branch in the primary Cys-loop channel tree, outside the explicitly identified core and divergent nicotinic acetylcholine-receptor groups.
Reason: NtR occupies a distinct unclassified branch in the primary Cys-loop channel tree, outside the explicitly identified core and divergent nicotinic acetylcholine-receptor groups. This is target-specific uncertainty about the placement of ligand/selectivity functions on the ancestral lineage: broad channel homology does not resolve acetylcholine gating or calcium permeability for this branch. No target ligand or ion-selectivity assay was found. The specific IBA is neither confirmed nor refuted; broad ligand-gated channel function remains supported. The Falcon report found no direct assay, but its broader skepticism about channel membership is not adopted; the actual uncertainty is the NTR branch-specific functional assignment.
Propagation Review
Root cause:UNRESOLVED
Sources checked:
PANTHER:PTN001825467UNRESOLVED
The descendant-supported ancestral assertion remains under review for the target-specific lineage/functional scope described in the rationale; donor number and target self-inclusion are not objections.
Supporting Evidence:
file:DROME/NtR/NtR-family-evidence.md
The published Cys-loop ligand-gated ion-channel tree in Matthews et al. (2018), Extended Data Figure 10d, includes Dmel NTR as a distinct branch outside both shaded nicotinic acetylcholine-receptor groups.
file:DROME/NtR/NtR-flybase.txt
UNCLASSIFIED LIGAND-GATED ION CHANNEL SUBUNITS
file:DROME/NtR/NtR-deep-research-falcon.md
No ligand-binding or electrophysiological experiment establishes association with a neuronal channel.
Summary: NtR is an unclassified Cys-loop ligand-gated channel subunit in the published insect channel-family tree.
Reason: NtR is an unclassified Cys-loop ligand-gated channel subunit in the published insect channel-family tree. Its ligand-binding architecture and membrane-spanning C-terminal region support a plasma-membrane ion-channel role and consequent membrane-potential regulation by conserved family inference. The ligand and ion selectivity remain unresolved.
Supporting Evidence:
file:DROME/NtR/NtR-family-evidence.md
The published Cys-loop ligand-gated ion-channel tree in Matthews et al. (2018), Extended Data Figure 10d, includes Dmel NTR as a distinct branch outside both shaded nicotinic acetylcholine-receptor groups.
Summary: NtR is an unclassified Cys-loop ligand-gated channel subunit in the published insect channel-family tree.
Reason: NtR is an unclassified Cys-loop ligand-gated channel subunit in the published insect channel-family tree. Its ligand-binding architecture and membrane-spanning C-terminal region support a plasma-membrane ion-channel role and consequent membrane-potential regulation by conserved family inference. The ligand and ion selectivity remain unresolved.
Supporting Evidence:
file:DROME/NtR/NtR-family-evidence.md
The published Cys-loop ligand-gated ion-channel tree in Matthews et al. (2018), Extended Data Figure 10d, includes Dmel NTR as a distinct branch outside both shaded nicotinic acetylcholine-receptor groups.
Summary: This synaptic assignment is generated downstream of the specific cholinergic channel inference.
Reason: This synaptic assignment is generated downstream of the specific cholinergic channel inference. NtR is a distinct unclassified Cys-loop channel branch, and its native synaptic localization, ligand and ion selectivity are not established. The propagated postsynaptic/excitatory context therefore remains unresolved even though a general plasma-membrane channel role is well supported. The Falcon report found no direct assay, but its broader skepticism about channel membership is not adopted; the actual uncertainty is the NTR branch-specific functional assignment.
Supporting Evidence:
file:DROME/NtR/NtR-family-evidence.md
The published Cys-loop ligand-gated ion-channel tree in Matthews et al. (2018), Extended Data Figure 10d, includes Dmel NTR as a distinct branch outside both shaded nicotinic acetylcholine-receptor groups.
file:DROME/NtR/NtR-flybase.txt
UNCLASSIFIED LIGAND-GATED ION CHANNEL SUBUNITS
file:DROME/NtR/NtR-deep-research-falcon.md
No ligand-binding or electrophysiological experiment establishes association with a neuronal channel.
GO:0060078 regulation of postsynaptic membrane potential
IEA GO_REF:0000108
UNDECIDED
Summary: This synaptic assignment is generated downstream of the specific cholinergic channel inference.
Reason: This synaptic assignment is generated downstream of the specific cholinergic channel inference. NtR is a distinct unclassified Cys-loop channel branch, and its native synaptic localization, ligand and ion selectivity are not established. The propagated postsynaptic/excitatory context therefore remains unresolved even though a general plasma-membrane channel role is well supported. The Falcon report found no direct assay, but its broader skepticism about channel membership is not adopted; the actual uncertainty is the NTR branch-specific functional assignment.
Supporting Evidence:
file:DROME/NtR/NtR-family-evidence.md
The published Cys-loop ligand-gated ion-channel tree in Matthews et al. (2018), Extended Data Figure 10d, includes Dmel NTR as a distinct branch outside both shaded nicotinic acetylcholine-receptor groups.
file:DROME/NtR/NtR-flybase.txt
UNCLASSIFIED LIGAND-GATED ION CHANNEL SUBUNITS
file:DROME/NtR/NtR-deep-research-falcon.md
No ligand-binding or electrophysiological experiment establishes association with a neuronal channel.
Summary: This synaptic assignment is generated downstream of the specific cholinergic channel inference.
Reason: This synaptic assignment is generated downstream of the specific cholinergic channel inference. NtR is a distinct unclassified Cys-loop channel branch, and its native synaptic localization, ligand and ion selectivity are not established. The propagated postsynaptic/excitatory context therefore remains unresolved even though a general plasma-membrane channel role is well supported. The Falcon report found no direct assay, but its broader skepticism about channel membership is not adopted; the actual uncertainty is the NTR branch-specific functional assignment.
Supporting Evidence:
file:DROME/NtR/NtR-family-evidence.md
The published Cys-loop ligand-gated ion-channel tree in Matthews et al. (2018), Extended Data Figure 10d, includes Dmel NTR as a distinct branch outside both shaded nicotinic acetylcholine-receptor groups.
file:DROME/NtR/NtR-flybase.txt
UNCLASSIFIED LIGAND-GATED ION CHANNEL SUBUNITS
file:DROME/NtR/NtR-deep-research-falcon.md
No ligand-binding or electrophysiological experiment establishes association with a neuronal channel.
Summary: This synaptic assignment is generated downstream of the specific cholinergic channel inference.
Reason: This synaptic assignment is generated downstream of the specific cholinergic channel inference. NtR is a distinct unclassified Cys-loop channel branch, and its native synaptic localization, ligand and ion selectivity are not established. The propagated postsynaptic/excitatory context therefore remains unresolved even though a general plasma-membrane channel role is well supported. The Falcon report found no direct assay, but its broader skepticism about channel membership is not adopted; the actual uncertainty is the NTR branch-specific functional assignment.
Supporting Evidence:
file:DROME/NtR/NtR-family-evidence.md
The published Cys-loop ligand-gated ion-channel tree in Matthews et al. (2018), Extended Data Figure 10d, includes Dmel NTR as a distinct branch outside both shaded nicotinic acetylcholine-receptor groups.
file:DROME/NtR/NtR-flybase.txt
UNCLASSIFIED LIGAND-GATED ION CHANNEL SUBUNITS
file:DROME/NtR/NtR-deep-research-falcon.md
No ligand-binding or electrophysiological experiment establishes association with a neuronal channel.
GO:0099565 chemical synaptic transmission, postsynaptic
IEA GO_REF:0000108
UNDECIDED
Summary: This synaptic assignment is generated downstream of the specific cholinergic channel inference.
Reason: This synaptic assignment is generated downstream of the specific cholinergic channel inference. NtR is a distinct unclassified Cys-loop channel branch, and its native synaptic localization, ligand and ion selectivity are not established. The propagated postsynaptic/excitatory context therefore remains unresolved even though a general plasma-membrane channel role is well supported. The Falcon report found no direct assay, but its broader skepticism about channel membership is not adopted; the actual uncertainty is the NTR branch-specific functional assignment.
Supporting Evidence:
file:DROME/NtR/NtR-family-evidence.md
The published Cys-loop ligand-gated ion-channel tree in Matthews et al. (2018), Extended Data Figure 10d, includes Dmel NTR as a distinct branch outside both shaded nicotinic acetylcholine-receptor groups.
file:DROME/NtR/NtR-flybase.txt
UNCLASSIFIED LIGAND-GATED ION CHANNEL SUBUNITS
file:DROME/NtR/NtR-deep-research-falcon.md
No ligand-binding or electrophysiological experiment establishes association with a neuronal channel.
Core Functions
Contributes to a Cys-loop ligand-gated ion channel; activating ligand and ion selectivity remain unresolved.
The published Cys-loop ligand-gated ion-channel tree in Matthews et al. (2018), Extended Data Figure 10d, includes Dmel NTR as a distinct branch outside both shaded nicotinic acetylcholine-receptor groups.
Q: Does the distinct NTR branch retain acetylcholine gating, calcium permeability or a postsynaptic role? Adjudicate the primary channel tree and PAINT ancestral placements independently of the established broad Cys-loop channel inference.
External Prediction Reviews
These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.
The generic ligand-gated channel prediction is supported by Cys-loop channel architecture, while ligand identity, calcium permeability and cholinergic signaling remain unresolved.
Review score: 2 = concordant with evidence; 1 = uncertain; 0 = discordant with evidence. This is an assessment score, not a model probability.
GO:0005230 extracellular ligand-gated monoatomic ion channel activityGO_MF
CNN — Correct but not novel Review score: 2/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-08
Review rationale: The generic ligand-gated channel claim is supported by the published Cys-loop channel-family tree, which includes Dmel NTR, and the target ligand-binding/channel architecture. It already appears in the exact-accession GOA record. NtR lies outside the identified nicotinic receptor groups, so this broad result does not validate the narrower acetylcholine-gating or calcium-permeability annotations. The OpenScientist audit reached the same split, retaining broad channel terms and downscoping the acetylcholine, calcium and cholinergic assignments as untested computational propagation.
Supporting Evidence:
file:DROME/NtR/NtR-family-evidence.md: "The published Cys-loop ligand-gated ion-channel tree in Matthews et al. (2018), Extended Data Figure 10d, includes Dmel NTR as a distinct branch outside both shaded nicotinic acetylcholine-receptor groups."
PMID:30429615: "Many insecticides act on ion channels, and we curated members of the Cys-loop ligand-gated ion channel (Cys-loop LGIC) superfamily in AaegL5."
file:DROME/NtR/NtR-hypotheses/ntr-cholinergic-calcium-and-synaptic-functions/openscientist.md: "NtR is a *bona fide* member of the Cys-loop ligand-gated ion channel (LGIC) superfamily: it has a *bona fide* extracellular neurotransmitter-gated ion-channel ligand-binding domain (Pfam PF02931), one canonical Cys-loop signature (C337–x13–C351), and a four-transmembrane-helix C-terminal region (M1–M4) in the expected Cys-loop topology"