CNGA1 is the pore-forming alpha subunit of the rod photoreceptor cyclic-nucleotide-gated cation channel. Three CNGA1 subunits assemble with one CNGB1 subunit in the native channel at the rod outer-segment plasma membrane. Intracellular cGMP binding promotes pore opening and cation influx; the light-driven fall in cGMP closes the channel and reduces the rod dark current. CNGA1 can also form functional homomeric channels in expression systems. Human pathogenic variants can impair channel abundance, targeting or function and cause recessive retinitis pigmentosa.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001750 photoreceptor outer segment | IEA GO_REF:0000107 | ACCEPT | Summary: Accept conserved photoreceptor outer-segment localization. Reason: The supplied mouse Cnga1/P29974 orthology source has direct outer-segment localization evidence. The inspected mouse retinal immunostaining and membrane-fraction study detects CNGA1 in rod outer segments and shows marked loss after Cngb1 deletion. Human CNGA1 channel function and plasma-membrane targeting independently support the conserved rod-channel context; the exact historical Ensembl transfer was not reconstructed. |
| GO:0005216 monoatomic ion channel activity | IEA GO_REF:0000002 | MODIFY | Summary: Refine the broad channel mapping to cGMP-gated cation-channel activity. Reason: The InterPro channel-family mapping captures a real pore-forming function. Human CNGA1 homomer and CNGA1/CNGB1 electrophysiology establish cGMP-dependent cation conduction, providing a more informative activity than the general ion-channel term. The physiological core is represented at assembled-channel scope. Proposed replacements: intracellularly cGMP-activated cation channel activity |
| GO:0005221 intracellularly cyclic nucleotide-activated monoatomic cation channel activity | IEA GO_REF:0000002 | MODIFY | Summary: Refine cyclic-nucleotide gating to the demonstrated cGMP-gated activity. Reason: The InterPro mapping is compatible with the human structural and functional studies, which directly connect cGMP binding to pore opening. cAMP can bind and partly activate the heteromer at high concentrations, but cGMP gating represents the principal rod-channel activity. Proposed replacements: intracellularly cGMP-activated cation channel activity |
| GO:0005222 intracellularly cAMP-activated cation channel activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retain the inherited cAMP-responsive channel capability. Reason: The current target itself has experimental grounding: human CNGA1/CNGB1 is partially activated by high cAMP, whereas CNGA1 homomers respond poorly. This supports the inherited capability at assembled-channel scope while cGMP gating defines the physiological core. Target inclusion among descendant evidence is legitimate. The historical PAINT node and alignment were not reconstructed. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000025806 SUPPORTS TRANSFER Qualified support from independent target channel/localization experiments, as detailed in this row. The historical PTN node, tree and alignment were not inspected; this does not claim a reconstruction of the ancestral placement. |
| GO:0005222 intracellularly cAMP-activated cation channel activity | IDA PMID:34699778 Structural mechanisms of assembly, permeation, gating, and p... | KEEP AS NON CORE | Summary: Retain directly measured partial activation by cAMP. Reason: Actual human-channel patch-clamp experiments show partial activation of the CNGA1/CNGB1 heteromer by high cAMP and little activation of the CNGA1 homomer. The cAMP-bound closed structural state does not refute that measured partial response. This is a supported secondary agonist capability rather than a separate physiological core. Supporting Evidence: |
| GO:0005223 intracellularly cGMP-activated cation channel activity | IBA GO_REF:0000033 | ACCEPT | Summary: Accept inherited cGMP-gated channel activity. Reason: Direct human CNGA1 and CNGA1/CNGB1 current measurements independently establish this activity, including the target self-donor. The physiological heteromer and experimentally functional CNGA1 homotetramer are distinguished. The historical PAINT node placement remains uninspected; no inference of weakness follows from donor count or target self-inclusion. The authentic PMID:1379636 abstract independently reports functional human full-length cDNA channels in 293S cells; its shorter splice construct was nonfunctional. This is functional-expression evidence, not an isolated ligand-binding affinity measurement. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000811708 SUPPORTS TRANSFER Qualified support from independent target channel/localization experiments, as detailed in this row. The historical PTN node, tree and alignment were not inspected; this does not claim a reconstruction of the ancestral placement. |
| GO:0005223 intracellularly cGMP-activated cation channel activity | IDA PMID:34699778 Structural mechanisms of assembly, permeation, gating, and p... | ACCEPT | Summary: Accept direct human cGMP-gated channel activity. Reason: The study measures cGMP activation of recombinant human CNGA1/CNGB1 and CNGA1 homomeric channels. Cryo-EM and electrophysiology together support ligand-dependent pore opening. Structural constructs use the paperβs historical NP_000078.2 coordinates 145β690, separately from current P29973 numbering; full-length functional comparisons are explicitly reported. Supporting Evidence: PMID:34699778 cGMP can fully activate both CNGA1 and CNGA1/B1 |
| GO:0005223 intracellularly cGMP-activated cation channel activity | ISS GO_REF:0000024 | ACCEPT | Summary: Accept the bovine CNGA1-supported contribution to cGMP-gated conductance. Reason: The exact donor Q00194 is bovine CNGA1. Its cloned alpha subunit produces cGMP-activated currents in Xenopus oocytes, both alone and with beta, in the inspected original Methods and Results. This supports the conserved human channel contribution, independently corroborated by direct human experiments. The source contributes_to qualifier is preserved. |
| GO:0005223 intracellularly cGMP-activated cation channel activity | ISS GO_REF:0000024 | ACCEPT | Summary: Accept the channel-complex contribution supported by bovine CNGB1. Reason: Q28181 is the bovine beta subunit, a component of the same rod-channel complex rather than a CNGA1 ortholog. The weaker contributes_to assertion is independently established for human CNGA1 by direct assembly and currents; it does not depend on treating CNGB1 as an alpha-subunit ortholog. The historical donor choice remains explicit. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q28181 SUPPORTS TRANSFER The authenticated bovine CNGB1 record carries experimental GO:0005223 (IDA, PMID:10352032), whose original experiments test bovine alpha/beta channels in oocytes. It supports the shared channel-complex activity, not alpha-subunit orthology or autonomous beta-channel activity. Independent human CNGA1 assembly and currents support the preserved contributes_to target assertion. The historical ISS selection itself was not reconstructed. |
| GO:0005515 protein binding | IPI PMID:20890309 Growth factor receptor-bound protein 14: a new modulator of ... | UNDECIDED | Summary: Positive GRB14 binding is established; attribution of the tested CNGA1 construct to the human target remains unresolved. Reason: Exact MINT records map P29973 to bovine GRB14/Q5ICW4 in positive physical assays. The original main text and supplement establish GRB14 association, but do not explicitly identify the CNGA1 plasmid species. The full-length forward and reverse primers agree with bovine CNGA1 terminal sequences rather than either inspected human RefSeq version; a separate CTR-primer discrepancy prevents treating primers as whole-plasmid sequencing. Human NP_000078.2 is 690 residues, so length alone is not diagnostic. The interaction is not rejected, and neither a wrong-gene conclusion nor a verified direct human pair is asserted. UNDECIDED concerns that source-to-target attribution, not the genericity of protein binding; the documented interaction is neither negated nor removed. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:20890309 Growth factor receptor-bound protein 14: a new modulator of ... | UNDECIDED | Summary: Positive GRB14 binding is established; attribution of the tested CNGA1 construct to the human target remains unresolved. Reason: Exact MINT records map P29973 to mouse Grb14/Q9JLM9 in positive physical assays. The original main text and supplement establish GRB14 association, but do not explicitly identify the CNGA1 plasmid species. The full-length forward and reverse primers agree with bovine CNGA1 terminal sequences rather than either inspected human RefSeq version; a separate CTR-primer discrepancy prevents treating primers as whole-plasmid sequencing. Human NP_000078.2 is 690 residues, so length alone is not diagnostic. The interaction is not rejected, and neither a wrong-gene conclusion nor a verified direct human pair is asserted. UNDECIDED concerns that source-to-target attribution, not the genericity of protein binding; the documented interaction is neither negated nor removed. Supporting Evidence: |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Accept inherited plasma-membrane activity. Reason: Human CNGA1 plasma-membrane targeting and excised-patch currents support the original activity location, with further assembly evidence from the human heteromer. Current descendant evidence includes the target itself; this is legitimate experimental grounding. Historical PAINT node placement is not reconstructed. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000811708 SUPPORTS TRANSFER Qualified support from independent target channel/localization experiments, as detailed in this row. The historical PTN node, tree and alignment were not inspected; this does not claim a reconstruction of the ancestral placement. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Accept plasma-membrane localization with the HPA confidence limit explicit. Reason: Current target-specific HPA ICC/IF data list plasma membrane as an additional location in human cell lines, but classify the overall staining reliability as uncertain. The compartment is nevertheless independently supported by original human CNGA1 transfection, surface immunofluorescence and functional membrane-patch measurements. HPA image pixels were not inspected. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Accept the UniProt plasma-membrane mapping. Reason: The supplied SL-0039 mapping agrees with direct human plasma-membrane immunofluorescence and cGMP-dependent membrane currents. The more specialized rod outer-segment membrane is retained separately. |
| GO:0005886 plasma membrane | TAS PMID:7479749 Mutations in the gene encoding the alpha subunit of the rod ... | ACCEPT | Summary: Accept the original human plasma-membrane localization. Reason: Original scanned Methods, Results and Figure 3/Table 2 pages were inspected. Wild-type human CNGA1 expressed in HEK293 cells shows predominantly surface staining and cGMP-gated currents; S316F and the Arg654 deletion constructs show reduced functional-channel yield and predominantly intracellular staining. Mutant targeting defects do not negate wild-type localization. Supporting Evidence: |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2514865 | ACCEPT | Summary: Accept the modeled plasma-membrane channel component. Reason: The actual Reactome event models cGMP dissociation from the channel. Its nested channel complex contains three human CNGA1 components and one CNGB1 at the plasma membrane, consistent with direct human channel studies. This is a location assertion; the calmodulin interaction in the regulatory event is attributed to the beta subunit, not independently assigned to CNGA1. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2514867 | ACCEPT | Summary: Accept the modeled plasma-membrane channel component. Reason: The actual Reactome event models sodium and calcium entry through the cGMP-bound channel. Its nested channel complex contains three human CNGA1 components and one CNGB1 at the plasma membrane, consistent with direct human channel studies. This is a location assertion; the calmodulin interaction in the regulatory event is attributed to the beta subunit, not independently assigned to CNGA1. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3229181 | ACCEPT | Summary: Accept the modeled plasma-membrane channel component. Reason: The actual Reactome event models calmodulin association with the channel complex. Its nested channel complex contains three human CNGA1 components and one CNGB1 at the plasma membrane, consistent with direct human channel studies. This is a location assertion; the calmodulin interaction in the regulatory event is attributed to the beta subunit, not independently assigned to CNGA1. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-74031 | ACCEPT | Summary: Accept the modeled plasma-membrane channel component. Reason: The actual Reactome event models cGMP binding to the channel. Its nested channel complex contains three human CNGA1 components and one CNGB1 at the plasma membrane, consistent with direct human channel studies. This is a location assertion; the calmodulin interaction in the regulatory event is attributed to the beta subunit, not independently assigned to CNGA1. |
| GO:0006811 monoatomic ion transport | IEA GO_REF:0000002 | MODIFY | Summary: Refine ion transport to cation transmembrane transport. Reason: The InterPro channel-family mapping is supported by direct cGMP-dependent cation currents. The performed step crosses a membrane, and the established permeant class is cations rather than ions without charge specificity. Proposed replacements: monoatomic cation transmembrane transport |
| GO:0006814 sodium ion transport | ISS GO_REF:0000024 | MODIFY | Summary: Refine sodium transport to sodium transmembrane transport. Reason: The exact bovine CNGA1 donor Q00194 was expressed in Xenopus oocytes. Original inside-out patch experiments measured cGMP-dependent currents under defined sodium solutions and biionic gradients. The human ortholog also forms a conducting cation pore; the refinement identifies the membrane-crossing step without changing the source evidence. Proposed replacements: sodium ion transmembrane transport |
| GO:0006816 calcium ion transport | ISS GO_REF:0000024 | MODIFY | Summary: Refine calcium transport to calcium ion transmembrane transport. Reason: The bovine CNGA1 donor experiments directly estimated calcium-to-sodium permeability from reversal potentials in recombinant alpha and alpha/beta channels, with oocyte calcium-activated chloride-current contamination controlled. This is distinct from calcium block or structural ion occupancy alone. Conserved human channel contribution supports the transmembrane refinement; species and assembled-channel scope remain explicit. Proposed replacements: calcium ion transmembrane transport Supporting Evidence: GO_REF:0000024 PMID:10352032 We expressed bovine rod Ξ± or Ξ±Ξ² channels in Xenopus oocytes |
| GO:0007601 visual perception | IMP PMID:11379879 Segregation of a mutation in CNGB1 encoding the beta-subunit... | ACCEPT | Summary: Retain visual perception using independent direct CNGA1 evidence. Reason: Full original PMID:11379879 concerns a CNGB1 mutation and does not report a direct CNGA1 perturbation experiment; its source-specific relationship is adjudicated as miscited. Independent original PMID:7479749 directly reports human CNGA1 retinitis-pigmentosa variants, impaired channel expression and targeting. Together with direct cGMP-gated channel function, that evidence supports the existing visual role without rewriting the original source assertion. |
| GO:0007601 visual perception | TAS PMID:7479749 Mutations in the gene encoding the alpha subunit of the rod ... | ACCEPT | Summary: Accept the directly supported role in vision. Reason: The original human family and recombinant-channel study links CNGA1 mutations to recessive retinitis pigmentosa and demonstrates impaired functional-channel yield and surface targeting. CNGA1 supplies the cGMP-gated pore that converts the rod phototransduction signal into membrane current, so this is performed visual signaling rather than a disease association alone. |
| GO:0007606 sensory perception of chemical stimulus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retain the inherited chemical-sensory context outside the representative rod core. Reason: The saved PTHR45638 PAINT records place GO:0007606 at bilaterian node PTN000025806 (IBD, 20250408) and record its loss at PTN002900733 (IRD, same date). The inspected PANTHER v19 tree places human CNGA1/P29973 below the gain in SF9, outside that loss branch; human CNGA3/Q16281 lies within the SF6 loss branch. Thus the cone-subfamily loss is a useful comparator but does not establish loss in rod CNGA1. Retain the positive curated inheritance outside the independently established rod visual core. Rod expression and intracellular cyclic-nucleotide recognition do not independently demonstrate either chemosensory function or its exhaustive absence. The original curator session and residue-level loss rationale were not recovered; no direct human chemosensory assay is claimed. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000025806 SUPPORTS TRANSFER PTN000025806 carries the explicit GO:0007606 IBD assertion. The current family tree places the sequence-authenticated P29973 leaf PTN002469207 below that node and outside the recorded PTN002900733/SF6 loss. This supports the existing curated transfer, not a newly established human chemosensory experiment. The available node records and current tree/alignment replace the earlier unresolved-placement statement; they do not reconstruct the historical curator rationale. Supporting Evidence: GO_REF:0000033 |
| GO:0016020 membrane | IEA GO_REF:0000120 | MODIFY | Summary: Refine the broad membrane mapping to plasma membrane. Reason: The combined automated sources supply membrane topology and rod-channel context. Direct human surface immunofluorescence and excised-patch currents establish the more informative plasma-membrane location; this refinement does not depend on reconstructing the ARBA rule or historical Ensembl mapping. Proposed replacements: plasma membrane |
| GO:0017071 intracellular cyclic nucleotide activated cation channel complex | IBA GO_REF:0000033 | ACCEPT | Summary: Accept membership in the cyclic-nucleotide-gated channel complex. Reason: The human channel structure and functional preparation establish a 3:1 CNGA1:CNGB1 assembly. This independently supports the inherited complex membership while leaving the historical PAINT node placement uninspected. The homotetrameric experimental capability is distinguished from the physiological heteromer. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000811708 SUPPORTS TRANSFER Qualified support from independent target channel/localization experiments, as detailed in this row. The historical PTN node, tree and alignment were not inspected; this does not claim a reconstruction of the ancestral placement. |
| GO:0017071 intracellular cyclic nucleotide activated cation channel complex | ISS GO_REF:0000024 | ACCEPT | Summary: Accept conserved channel-complex membership from bovine CNGA1. Reason: The exact Q00194 donor participates in recombinant bovine alpha/beta CNG channels with measurable cGMP-activated currents. Direct human structural evidence independently resolves the 3:1 assembly, avoiding transfer of a historical assumed stoichiometry. |
| GO:0030552 cAMP binding | IDA PMID:34699778 Structural mechanisms of assembly, permeation, gating, and p... | KEEP AS NON CORE | Summary: Retain direct cAMP binding as secondary ligand recognition. Reason: The human CNGA1/CNGB1 cAMP-bound structure establishes ligand occupancy, while functional recordings show only partial activation at high cAMP. Binding is therefore supported without making cAMP the principal rod physiological agonist or creating a redundant ligand-binding core. Supporting Evidence: |
| GO:0030553 cGMP binding | IBA GO_REF:0000033 | ACCEPT | Summary: Accept inherited cGMP binding. Reason: The human target has direct cGMP-bound structural evidence and ligand-dependent gating, so target inclusion in the donor list is legitimate experimental grounding. The binding capability forms part of the integrated cGMP-gated channel mechanism; the historical PAINT node is not independently reconstructed. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000025806 SUPPORTS TRANSFER Qualified support from independent target channel/localization experiments, as detailed in this row. The historical PTN node, tree and alignment were not inspected; this does not claim a reconstruction of the ancestral placement. |
| GO:0030553 cGMP binding | IDA PMID:34699778 Structural mechanisms of assembly, permeation, gating, and p... | ACCEPT | Summary: Accept cGMP recognition within the human channel. Reason: The source resolves cGMP-bound human CNGA1/CNGB1 and measures activation by cGMP. Ligand recognition in the CNGA1 cyclic-nucleotide-binding domain is part of the assembled pore-gating mechanism, not a separate enzymatic activity. Supporting Evidence: |
| GO:0042622 photoreceptor outer segment membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Accept the conserved outer-segment membrane location. Reason: The mouse Cnga1 donor and human rod-channel biology support a membrane-localized channel in the outer segment. Inspected mouse retinal immunostaining and membrane preparations corroborate this localization; direct human surface-channel experiments separately establish membrane insertion. Historical Ensembl transfer details were not reconstructed. |
| GO:0042622 photoreceptor outer segment membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Accept outer-segment membrane activity with the beta-subunit donor scope explicit. Reason: MGI:2664102 maps to mouse Cngb1, the beta subunit of the same rod-channel complex. It is not relabeled as a CNGA1 ortholog. Independent mouse CNGA1 outer-segment localization and direct human membrane-channel studies support the target location while preserving the original donor assertion. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:2664102 SUPPORTS TRANSFER This is mouse Cngb1, not a CNGA1 ortholog. Its authenticated current UniProt E1AZ71 record has experimental located_in GO:0042622 (IDA, PMID:19299621), supporting the shared compartment; that qualifier is not silently equated to is_active_in. Independent mouse CNGA1 staining in PMID:15634774 and human CNGA1 channel experiments support the target location/activity. The original source and is_active_in qualifier remain unchanged; the historical ISS selection was not reconstructed. |
| GO:0042622 photoreceptor outer segment membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Accept activity at the photoreceptor outer-segment membrane. Reason: MGI:88436 maps to mouse Cnga1/P29974. The inspected mouse localization study detects endogenous CNGA1 in the rod outer-segment layer and retinal membrane fractions. Human channel experiments independently corroborate the conserved membrane-channel function. Supporting Evidence: GO_REF:0000024 PMID:15634774 some residual CNGA1 immunolabeling detected in rod outer segments |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | MODIFY | Summary: Refine transmembrane transport to cation transmembrane transport. Reason: The channel-family mapping is supported by human cGMP-dependent currents and direct bovine permeability measurements. The performed transport is through a cation pore, so the cation-specific process is more informative than unrestricted transmembrane transport. Proposed replacements: monoatomic cation transmembrane transport |
| GO:0098655 monoatomic cation transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: Accept inherited cation transmembrane transport. Reason: Direct human channel currents and the bovine donor permeability experiments establish cation movement across membranes. These data support the target activity independently of unresolved historical fly/worm PAINT placements, which are not reconstructed here. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000811708 SUPPORTS TRANSFER Qualified support from independent target channel/localization experiments, as detailed in this row. The historical PTN node, tree and alignment were not inspected; this does not claim a reconstruction of the ancestral placement. |
| GO:0120200 rod photoreceptor outer segment | IEA GO_REF:0000107 | ACCEPT | Summary: Accept rod photoreceptor outer-segment localization. Reason: The supplied mouse Cnga1/P29974 source is the rod alpha subunit. Actual mouse immunostaining detects endogenous CNGA1 in rod outer segments and distinguishes cone CNGA3 expression. This supports the conserved rod-specific location together with the human rod-channel structural and functional evidence. |
| GO:0120200 rod photoreceptor outer segment | ISS GO_REF:0000024 | ACCEPT | Summary: Accept rod photoreceptor outer-segment localization. Reason: The supplied mouse Cnga1/P29974 source is the rod alpha subunit. Actual mouse immunostaining detects endogenous CNGA1 in rod outer segments and distinguishes cone CNGA3 expression. This supports the conserved rod-specific location together with the human rod-channel structural and functional evidence. |
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Download this section (compressed HTML)Q: Which CNGA1 species and exact sequence were used in the original GRB14 plasmids, and does sequence-verified human CNGA1 reproduce the interaction?
Suggested experts: Rod CNG-channel and GRB14 investigators
Q: Under which native rod conditions, if any, does cAMP measurably contribute to CNGA1/CNGB1 gating?
Suggested experts: Photoreceptor electrophysiologists
Q: What experimental descendants and ancestral placement underlie the chemical-sensory PAINT assertion for human CNGA1?
Suggested experts: CNG-family PAINT curators
Experiment: Sequence-verify human and bovine full-length CNGA1 and the corresponding C-terminal fragments, then compare matched GRB14 binding and cGMP-dependent currents with expression and localization controls. Keep isolated-domain binding distinct from native retinal regulation.
Hypothesis: Human CNGA1 retains the GRB14 contact reported for the original channel preparations.
Type: Construct-resolved interaction and electrophysiology
Experiment: Compare surface-normalized currents, ligand concentration responses and single-channel behavior for sequence-verified human variants in both homomeric and 3:1 CNGA1/CNGB1 preparations.
Hypothesis: Disease variants can affect surface abundance independently of single-channel gating.
Type: Surface quantification and patch-clamp analysis
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