id: Q03611
gene_symbol: tax-4
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: >-
  tax-4 encodes the alpha (principal, pore-forming) subunit of a cyclic
  nucleotide-gated (CNG) cation channel, the C. elegans ortholog of vertebrate
  CNGA subunits. The channel is opened directly by intracellular cGMP (and, with
  lower sensitivity, cAMP) rather than by membrane voltage, and conducts Ca2+,
  Na+ and K+ across the membrane; a functionally important pore glutamate forms
  the selectivity filter and a C-linker gating ring couples cyclic-nucleotide
  binding in the cytoplasmic cyclic-nucleotide-binding domain to opening of the
  central gate. TAX-4 assembles as a homotetramer and can form a functional
  homomeric channel on its own, but in vivo it partners with the modulatory beta
  subunit TAX-2 (which cannot form a channel alone) to build the native sensory
  channel; the TAX-4/TAX-2 heteromer is markedly less cGMP-sensitive than the
  TAX-4 homomer. TAX-4 is expressed in many ciliated sensory neurons and is
  concentrated at their sensory endings, in the non-motile sensory cilium
  (including an inversin/NPHP-2-anchored proximal ciliary compartment in the AFD
  thermosensory neuron) and in dendrites. As the effector channel of
  cGMP-mediated signal transduction, TAX-4 is required for a broad range of
  sensory modalities, including thermosensation and thermotaxis, chemosensation
  and chemotaxis (including detection of CO2), oxygen sensing and aerotaxis, and
  light responses (phototransduction) in specific neurons; channel activity also
  feeds into downstream outputs such as sensory-neuron gene expression and the
  maintenance of sensory axon structure.
existing_annotations:
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      TAX-4 is a plasma-membrane cyclic nucleotide-gated cation channel; gating
      cation flux across the plasma membrane at sensory endings is its site of
      action. Correct and core.
    action: ACCEPT
- term:
    id: GO:0007606
    label: sensory perception of chemical stimulus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Chemosensation is a defining role of TAX-4: tax-4 mutants fail responses to
      water-soluble and volatile chemical attractants. Core process.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:8893027
      supporting_text: >-
        The C. elegans tax-4 mutants are abnormal in multiple sensory behaviors:
        they fail to respond to temperature or to water-soluble or volatile
        chemical attractants.
- term:
    id: GO:0005222
    label: intracellularly cAMP-activated cation channel activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      TAX-4 is a cyclic-nucleotide-gated channel that can also be activated by
      cAMP, though cGMP is the physiologically relevant ligand and the channel is
      cGMP-selective. Retained as a genuine (if secondary) channel activity.
    action: ACCEPT
- term:
    id: GO:0005223
    label: intracellularly cGMP-activated cation channel activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      This is the core molecular function of TAX-4: a directly cGMP-gated cation
      channel that is the effector of cGMP sensory signal transduction.
    action: ACCEPT
- term:
    id: GO:0030553
    label: cGMP binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      TAX-4 has a cyclic-nucleotide-binding domain that binds cGMP to open the
      gate; cGMP binding is directly demonstrated by the cGMP-bound structures.
      Core.
    action: ACCEPT
- term:
    id: GO:0098655
    label: monoatomic cation transmembrane transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      The channel conducts Ca2+, Na+ and K+ (non-selective cation permeation);
      monoatomic cation transmembrane transport is the accurate transport-process
      term. Core.
    action: ACCEPT
- term:
    id: GO:0017071
    label: intracellular cyclic nucleotide activated cation channel complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: >-
      TAX-4 is a subunit of the cyclic-nucleotide-gated cation channel complex
      (homotetramer in vitro; native TAX-4/TAX-2 heteromer). Correct complex term.
    action: ACCEPT
- term:
    id: GO:0005216
    label: monoatomic ion channel activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Accurate but generic parent of the specific cGMP-gated cation channel
      activity. Retained; the informative term is GO:0005223.
    action: ACCEPT
- term:
    id: GO:0005221
    label: intracellularly cyclic nucleotide-activated monoatomic cation channel activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Accurate family-level CNG channel molecular-function term; a direct parent
      of the cGMP- and cAMP-activated specific terms already annotated.
    action: ACCEPT
- term:
    id: GO:0005249
    label: voltage-gated potassium channel activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Incorrect. TAX-4 is a non-selective cation CNG channel, NOT a
      voltage-gated, K+-selective channel. The cryo-EM structure shows an unusual
      voltage-sensor-like domain accounting for its deficient voltage dependence.
      This IEA term is an over-propagation from the shared EAG/ELK/ERG-family
      InterPro signature and should be removed.
    action: REMOVE
    supported_by:
    - reference_id: PMID:28099415
      supporting_text: >-
        The channel has an unusual voltage-sensor-like domain, accounting for its
        deficient voltage dependence.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Plasma-membrane localization (UniProt subcellular-location mapping),
      consistent with the cryo-EM cell-membrane assignment and ciliary/dendritic
      membrane localization. Correct and core.
    action: ACCEPT
- term:
    id: GO:0005929
    label: cilium
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      TAX-4 localizes to sensory cilia; a more specific experimental term
      (non-motile cilium, GO:0097730) is also annotated. Correct.
    action: ACCEPT
- term:
    id: GO:0006811
    label: monoatomic ion transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      Accurate but generic parent of monoatomic cation transmembrane transport.
      Retained.
    action: ACCEPT
- term:
    id: GO:0006813
    label: potassium ion transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      Over-annotation. TAX-4 is a non-selective cation channel that does conduct
      K+, but it is not a dedicated potassium transporter; the K+-specific process
      term comes from the K-channel-family InterPro signature. The accurate term
      is monoatomic cation transmembrane transport (GO:0098655).
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: >-
      Generic membrane location; true but superseded by plasma membrane / cilium.
      Retained.
    action: ACCEPT
- term:
    id: GO:0034703
    label: cation channel complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: part_of
  review:
    summary: >-
      TAX-4 is part of a cation channel complex (the CNG channel). Correct;
      also supported experimentally (PMID:10064800).
    action: ACCEPT
- term:
    id: GO:0055085
    label: transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      Accurate but generic parent process. Retained.
    action: ACCEPT
- term:
    id: GO:0070482
    label: response to oxygen levels
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      The tax-2/tax-4 CNG channel is required for O2-evoked responses and
      hyperoxia avoidance; also supported experimentally. A downstream sensory
      output rather than the core channel function.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0071805
    label: potassium ion transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: >-
      Over-annotation, same rationale as GO:0006813: non-selective cation channel
      wrongly cast as a K+-specific transporter via the K-channel InterPro
      signature. Use monoatomic cation transmembrane transport (GO:0098655).
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:28099415
  qualifier: enables
  review:
    summary: >-
      Reflects TAX-4 self-association into a homotetramer, directly seen in the
      cryo-EM structure (PMID:28099415), which solved the channel as a
      homotetramer. Accurate but low-information on its own; the tetramer is
      captured better by the channel-complex terms (GO:0017071, GO:0034703).
      Kept as reported.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:32483338
  qualifier: enables
  review:
    summary: >-
      Duplicate self-association (homotetramer) evidence from the second cryo-EM
      structure. Kept as reported; non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0097730
    label: non-motile cilium
  evidence_type: IDA
  original_reference_id: PMID:31259686
  qualifier: located_in
  review:
    summary: >-
      TAX-4 is a ciliary CNG channel; UniProt records ciliary subcellular
      location from this study. Core cellular component.
    action: ACCEPT
- term:
    id: GO:0034703
    label: cation channel complex
  evidence_type: IDA
  original_reference_id: PMID:10064800
  qualifier: part_of
  review:
    summary: >-
      Functional reconstitution shows TAX-4 and TAX-2 form a heteromeric cation
      channel in cultured cells. Directly supports channel-complex membership.
      Core.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:10064800
      supporting_text: >-
        Here we show that TAX-4 and TAX-2 form a heteromeric channel when
        expressed in HEK293 cells, but TAX-2 does not form a channel on its own.
- term:
    id: GO:0003031
    label: detection of carbon dioxide
  evidence_type: IMP
  original_reference_id: PMID:24240097
  qualifier: involved_in
  review:
    summary: >-
      CO2 detection in BAG (and other) neurons requires the tax-2/tax-4 cGMP-gated
      channel downstream of the receptor guanylyl cyclase GCY-9. A specific
      chemosensory modality; retained as a downstream consequence of the core
      channel function. (Cited paper is abstract-only in the cache; the tax-4
      requirement for CO2 responses is independently established in PMID:21435556.)
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0019722
    label: calcium-mediated signaling
  evidence_type: IMP
  original_reference_id: PMID:24240097
  qualifier: involved_in
  review:
    summary: >-
      Channel opening admits Ca2+, driving the calcium signal in chemosensory
      neurons. A downstream signaling consequence of cation channel activity;
      non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:25303524
  qualifier: involved_in
  review:
    summary: >-
      In ASJ, TAX-4-dependent chemosensory signaling induces expression of the
      DAF-7/TGF-beta neuromodulator on exposure to P. aeruginosa metabolites. An
      indirect, activity-dependent transcriptional output; non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:25303524
      supporting_text: >-
        secondary metabolites produced by Pseudomonas aeruginosa modulates a
        neuroendocrine signaling pathway that promotes avoidance behavior
- term:
    id: GO:0050907
    label: detection of chemical stimulus involved in sensory perception
  evidence_type: IMP
  original_reference_id: PMID:24240097
  qualifier: involved_in
  review:
    summary: >-
      TAX-4 is the effector channel for detection of chemical stimuli in sensory
      neurons; an accurate general term for its core sensory role. Core.
    action: ACCEPT
- term:
    id: GO:0007602
    label: phototransduction
  evidence_type: IMP
  original_reference_id: PMID:20436480
  qualifier: involved_in
  review:
    summary: >-
      In the ASJ photoreceptor neuron, light-evoked cGMP opens cGMP-sensitive CNG
      channels; TAX-4 is required for this response. A specialized downstream
      sensory modality; non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:20436480
      supporting_text: >-
        opening of cGMP-sensitive CNG channels and stimulation of photoreceptor
        cells.
- term:
    id: GO:0007199
    label: G protein-coupled receptor signaling pathway coupled to cGMP nucleotide
      second messenger
  evidence_type: IMP
  original_reference_id: PMID:20436480
  qualifier: involved_in
  review:
    summary: >-
      TAX-4 acts as the cGMP-gated effector at the end of a G-protein/cGMP
      phototransduction cascade in ASJ. Retained as a downstream pathway role;
      non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:20436480
      supporting_text: >-
        phototransduction in ASJ is a G protein-mediated process and requires
        membrane-associated guanylate cyclases
- term:
    id: GO:0040040
    label: thermosensory behavior
  evidence_type: IMP
  original_reference_id: PMID:21315599
  qualifier: involved_in
  review:
    summary: >-
      Mutations in the tax-4 CNG channel abolish AFD thermosensitivity and
      isothermal tracking (per this study's electrophysiology and behavior).
      Thermosensation is a flagship sensory role of TAX-4. Core.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:21315599
      supporting_text: >-
        These results indicate that the AFD neurons and TAX-4 CNG channel are
        required to both initiate and maintain isothermal tracks.
- term:
    id: GO:0043052
    label: thermotaxis
  evidence_type: IMP
  original_reference_id: PMID:21315599
  qualifier: involved_in
  review:
    summary: >-
      Thermotaxis (isothermal tracking) is the behavioral output of AFD
      thermosensation that requires TAX-4. A downstream behavior; non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0010754
    label: negative regulation of receptor guanylyl cyclase signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:23940325
  qualifier: involved_in
  review:
    summary: >-
      In O2-sensing neurons, cGMP-gated channel activity (Ca2+ entry) drives
      Ca2+-dependent negative-feedback loops that shape cGMP dynamics. A feedback
      role secondary to the core channel function; non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:23940325
      supporting_text: >-
        Increased cGMP leads to a sustained Ca(2+) response in the neuron that
        depends on cGMP-gated ion channels.
- term:
    id: GO:0070482
    label: response to oxygen levels
  evidence_type: IMP
  original_reference_id: PMID:23940325
  qualifier: involved_in
  review:
    summary: >-
      TAX-4-containing cGMP-gated channels transduce O2-evoked cGMP into sustained
      Ca2+ responses in the gas-sensing neuron. Downstream sensory output;
      non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0040010
    label: positive regulation of growth rate
  evidence_type: IGI
  original_reference_id: PMID:15530424
  qualifier: involved_in
  review:
    summary: >-
      Genetic-interaction annotation from a study primarily on the cng-3 CNG
      channel and thermotolerance, with tax-4 as background. A pleiotropic
      physiological consequence; non-core. (Cited paper abstract-only in cache.)
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0097543
    label: ciliary inversin compartment
  evidence_type: IDA
  original_reference_id: PMID:25335890
  qualifier: located_in
  review:
    summary: >-
      In AFD, NPHP-2/inversin anchors the cGMP-gated ion channel within the
      proximal ciliary (inversin) compartment. Directly supports this specific
      ciliary sub-compartment localization. Core cellular component.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:25335890
      supporting_text: >-
        requires NPHP-2 (known as inversin in mammals) to anchor a cGMP-gated ion
        channel within the proximal ciliary region.
- term:
    id: GO:0097730
    label: non-motile cilium
  evidence_type: IDA
  original_reference_id: PMID:25335890
  qualifier: located_in
  review:
    summary: >-
      TAX-4/TAX-2 cGMP-gated channel localizes to the AFD sensory cilium. Core
      cellular component.
    action: ACCEPT
- term:
    id: GO:0005223
    label: intracellularly cGMP-activated cation channel activity
  evidence_type: IDA
  original_reference_id: PMID:10064800
  qualifier: enables
  review:
    summary: >-
      Direct functional reconstitution in cultured cells demonstrates a
      cGMP-gated cation channel. Core molecular function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:10064800
      supporting_text: >-
        The heteromeric TAX-4/TAX-2 channel is 25-fold less sensitive to cGMP
        than the TAX-4 channel, but it remains highly selective for cGMP over
        cAMP.
- term:
    id: GO:0098655
    label: monoatomic cation transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:10064800
  qualifier: involved_in
  review:
    summary: >-
      Reconstituted channel conducts cations across the membrane. Core transport
      process.
    action: ACCEPT
- term:
    id: GO:0097730
    label: non-motile cilium
  evidence_type: IDA
  original_reference_id: PMID:23886944
  qualifier: located_in
  review:
    summary: >-
      Study defines sequences and trans-acting factors required for ciliary
      targeting/localization of the TAX-4 CNGA and TAX-2 CNGB subunits. Directly
      supports ciliary localization. Core cellular component.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:23886944
      supporting_text: >-
        sequences required for efficient ciliary targeting and localization of
        the TAX-2 CNGB and TAX-4 CNGA subunits.
- term:
    id: GO:0006935
    label: chemotaxis
  evidence_type: IMP
  original_reference_id: PMID:21435556
  qualifier: involved_in
  review:
    summary: >-
      CO2-evoked responses and CO2 avoidance behavior require cGMP-gated channels
      containing TAX-2 and TAX-4. Chemotaxis is a behavioral output of the core
      chemosensory channel function; retained as non-core for this study.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:21435556
      supporting_text: >-
        CO(2)-evoked Ca(2+) responses in AFD and BAG neurons require cGMP-gated
        ion channels.
- term:
    id: GO:0070482
    label: response to oxygen levels
  evidence_type: IMP
  original_reference_id: PMID:19323996
  qualifier: involved_in
  review:
    summary: >-
      URX and BAG O2-sensing neurons use cGMP signaling (via sGCs) that is
      transduced by CNG channels; tax-4 is required for O2 responses. Downstream
      sensory output; non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0005222
    label: intracellularly cAMP-activated cation channel activity
  evidence_type: IDA
  original_reference_id: PMID:8893027
  qualifier: enables
  review:
    summary: >-
      TAX-4 expressed in cultured cells functions as a cyclic-nucleotide-gated
      channel (cAMP-responsive as well as cGMP-gated). Genuine channel activity,
      though cGMP is physiologically dominant.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:8893027
      supporting_text: >-
        Tax-4 protein expressed in cultured cells functions as a cyclic
        nucleotide-gated channel.
- term:
    id: GO:0005223
    label: intracellularly cGMP-activated cation channel activity
  evidence_type: IDA
  original_reference_id: PMID:8893027
  qualifier: enables
  review:
    summary: >-
      Original demonstration that TAX-4 forms a cyclic-nucleotide-gated channel;
      cGMP is the key intracellular messenger in worm sensory transduction. Core
      molecular function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:8893027
      supporting_text: >-
        The results suggest that a cyclic nucleotide-gated channel is required for
        thermosensation and chemosensation
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: IDA
  original_reference_id: PMID:8893027
  qualifier: located_in
  review:
    summary: >-
      TAX-4::GFP localizes at the sensory endings of thermosensory, gustatory and
      olfactory neurons (dendritic sensory endings/cilia). Core cellular component.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:8893027
      supporting_text: >-
        The Tax-4::GFP fusion is partly localized at the sensory endings of these
        neurons.
- term:
    id: GO:0097730
    label: non-motile cilium
  evidence_type: IDA
  original_reference_id: PMID:8893027
  qualifier: located_in
  review:
    summary: >-
      TAX-4 localizes to the sensory endings (cilia) of ciliated sensory neurons.
      Core cellular component.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:8893027
      supporting_text: >-
        expressed in thermosensory, gustatory, and olfactory neurons mediating all
        the sensory behaviors affected by the tax-4 mutations
- term:
    id: GO:0030516
    label: regulation of axon extension
  evidence_type: IMP
  original_reference_id: PMID:9486798
  qualifier: involved_in
  review:
    summary: >-
      tax-2/tax-4 are required to maintain correct sensory axon structure;
      mutants show inappropriate late-larval axon outgrowth. A pleiotropic
      developmental/maintenance role distinct from acute sensory transduction;
      non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:9486798
      supporting_text: >-
        tax-2 and tax-4 are required for the maintenance of correct axon
        structure
- term:
    id: GO:0009454
    label: aerotaxis
  evidence_type: IMP
  original_reference_id: PMID:15220933
  qualifier: involved_in
  review:
    summary: >-
      Avoidance of high oxygen requires the sensory cGMP-gated channel tax-2/tax-4
      plus the sGC gcy-35. Aerotaxis is a downstream O2-driven behavior; non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:15220933
      supporting_text: >-
        Avoidance of high oxygen levels by C. elegans requires the sensory
        cGMP-gated channel tax-2/tax-4 and a specific soluble guanylate cyclase
        homologue, gcy-35.
- term:
    id: GO:0055093
    label: response to hyperoxia
  evidence_type: IMP
  original_reference_id: PMID:15220933
  qualifier: involved_in
  review:
    summary: >-
      TAX-4-dependent O2 sensation mediates avoidance of hyperoxic environments.
      Downstream sensory output; non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0040040
    label: thermosensory behavior
  evidence_type: IMP
  original_reference_id: PMID:11879652
  qualifier: involved_in
  review:
    summary: >-
      Thermosensory behavior requiring TAX-4, assayed here in the context of the
      TAX-6 calcineurin gain-control pathway. Thermosensation is a core TAX-4
      sensory role.
    action: ACCEPT
- term:
    id: GO:0040040
    label: thermosensory behavior
  evidence_type: IGI
  original_reference_id: PMID:11879652
  qualifier: involved_in
  review:
    summary: >-
      Genetic-interaction (with tax-6) evidence corroborating TAX-4's core
      thermosensory-behavior role.
    action: ACCEPT
- term:
    id: GO:0042048
    label: olfactory behavior
  evidence_type: IMP
  original_reference_id: PMID:11879652
  qualifier: involved_in
  review:
    summary: >-
      Olfaction is one of the sensory modalities requiring TAX-4; here in the
      context of tax-6-mediated adaptation/gain control. A downstream behavioral
      output; non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0042048
    label: olfactory behavior
  evidence_type: IGI
  original_reference_id: PMID:11879652
  qualifier: involved_in
  review:
    summary: >-
      Genetic-interaction evidence for an olfactory-behavior role. Non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0043052
    label: thermotaxis
  evidence_type: IMP
  original_reference_id: PMID:11879652
  qualifier: involved_in
  review:
    summary: >-
      Thermotaxis behavior involving TAX-4 in the tax-6 gain-control study.
      Downstream behavior; non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0043052
    label: thermotaxis
  evidence_type: IGI
  original_reference_id: PMID:11879652
  qualifier: involved_in
  review:
    summary: >-
      Genetic-interaction evidence for a thermotaxis role. Non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0040040
    label: thermosensory behavior
  evidence_type: IMP
  original_reference_id: PMID:14711416
  qualifier: involved_in
  review:
    summary: >-
      CMK-1 and TAX-4 regulate AFD thermosensory-neuron gene expression,
      morphology and function. Thermosensation is a core TAX-4 role; well
      supported.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:14711416
      supporting_text: >-
        the CMK-1 Ca2+/calmodulin-dependent protein kinase I (CaMKI) and the TAX-4
        cyclic nucleotide-gated channel regulate gene expression, morphology, and
        functions of the AFD thermosensory neurons.
- term:
    id: GO:0045664
    label: regulation of neuron differentiation
  evidence_type: IMP
  original_reference_id: PMID:14711416
  qualifier: involved_in
  review:
    summary: >-
      TAX-4 activity is required to maintain AFD-specific gene expression and
      morphology; an activity-dependent effect on neuronal differentiation state
      rather than a direct role. Non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:14711416
  qualifier: involved_in
  review:
    summary: >-
      TAX-4 channel activity is required to maintain AFD-specific gene expression.
      This is an indirect, activity-dependent transcriptional consequence; TAX-4
      is a channel, not a transcriptional regulator. Non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:14711416
      supporting_text: >-
        TAX-4 functions are required during larval stages to maintain gene
        expression in the adult.
- term:
    id: GO:0048812
    label: neuron projection morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:14711416
  qualifier: involved_in
  review:
    summary: >-
      TAX-4 activity influences AFD sensory-ending morphology. A downstream,
      activity-dependent morphological effect; non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0007635
    label: chemosensory behavior
  evidence_type: IMP
  original_reference_id: PMID:8893027
  qualifier: involved_in
  review:
    summary: >-
      tax-4 mutants are defective in chemosensory behaviors (gustation and
      olfaction). Core sensory role.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:8893027
      supporting_text: >-
        The C. elegans tax-4 mutants are abnormal in multiple sensory behaviors:
        they fail to respond to temperature or to water-soluble or volatile
        chemical attractants.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: NAS
  original_reference_id: PMID:8893027
  qualifier: located_in
  review:
    summary: >-
      Generic membrane localization (NAS). True but superseded by plasma
      membrane / cilium / dendrite. Retained.
    action: ACCEPT
- term:
    id: GO:0030553
    label: cGMP binding
  evidence_type: NAS
  original_reference_id: PMID:8893027
  qualifier: enables
  review:
    summary: >-
      cGMP binding inferred (NAS) from the CNG-channel homology and cGMP-gated
      activity; later confirmed structurally. Core molecular function.
    action: ACCEPT
- term:
    id: GO:0040040
    label: thermosensory behavior
  evidence_type: IMP
  original_reference_id: PMID:8893027
  qualifier: involved_in
  review:
    summary: >-
      Original genetic evidence that tax-4 is required for thermosensation
      (mutants fail to respond to temperature). Core sensory role.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:8893027
      supporting_text: >-
        they fail to respond to temperature or to water-soluble or volatile
        chemical attractants.
core_functions:
- description: >-
    TAX-4 is the pore-forming alpha subunit of a cyclic nucleotide-gated (CNG)
    cation channel that is opened directly by intracellular cGMP and conducts
    Ca2+/Na+/K+ across the plasma membrane at the sensory endings, cilia and
    dendrites of ciliated sensory neurons, serving as the effector channel of
    cGMP-mediated sensory signal transduction. It assembles as a homotetramer and
    in vivo forms the native sensory channel together with the modulatory beta
    subunit TAX-2.
  molecular_function:
    id: GO:0005223
    label: intracellularly cGMP-activated cation channel activity
  directly_involved_in:
  - id: GO:0007606
    label: sensory perception of chemical stimulus
  - id: GO:0050907
    label: detection of chemical stimulus involved in sensory perception
  - id: GO:0098655
    label: monoatomic cation transmembrane transport
  locations:
  - id: GO:0005886
    label: plasma membrane
  - id: GO:0097730
    label: non-motile cilium
  - id: GO:0030425
    label: dendrite
  in_complex:
    id: GO:0017071
    label: intracellular cyclic nucleotide activated cation channel complex
  supported_by:
  - reference_id: PMID:8893027
    supporting_text: >-
      Tax-4 protein expressed in cultured cells functions as a cyclic
      nucleotide-gated channel.
  - reference_id: PMID:10064800
    supporting_text: >-
      with TAX-4 as the alpha subunit and TAX-2 acting as a modifying beta
      subunit.
  - reference_id: PMID:28099415
    supporting_text: >-
      a cyclic-nucleotide-gated channel from Caenorhabditis elegans in the cyclic
      guanosine monophosphate (cGMP)-bound open state.
- description: >-
    TAX-4 binds cGMP through its cytoplasmic cyclic-nucleotide-binding domain;
    ligand binding drives the conformational change (via the C-linker gating
    ring) that opens the central gate, making cGMP binding the ligand-sensing
    step of the channel's activity.
  molecular_function:
    id: GO:0030553
    label: cGMP binding
  supported_by:
  - reference_id: PMID:28099415
    supporting_text: >-
      A carboxy-terminal linker connecting S6 and the cyclic-nucleotide-binding
      domain interacts directly with both the voltage-sensor-like domain and the
      pore domain
  - reference_id: PMID:32483338
    supporting_text: >-
      Mechanism of ligand activation of a eukaryotic cyclic nucleotide-gated
      channel.
  knowledge_gaps:
  - gap_statement: >-
      The in vivo subunit stoichiometry and arrangement of the native sensory CNG
      channel (the TAX-4:TAX-2 ratio in the tetramer, and whether it varies
      between neurons or even between ciliary subcompartments of one neuron) is
      not established.
    boundary: >-
      TAX-4 forms homotetramers in vitro and in cryo-EM structures, and TAX-4 +
      TAX-2 co-assemble into a functional heteromer in HEK293 cells while TAX-2
      alone cannot form a channel; but the composition of the endogenous channel
      in worm cilia is inferred, not measured.
    gap_kind:
    - BIOLOGY
    dark_aspect: RESIDUAL_SUBGAP
    status: OPEN
    significance: >-
      Subunit composition sets ligand sensitivity, ion handling and localization,
      so it directly determines how each sensory neuron converts a cGMP signal
      into a response.
    resolution: >-
      Native-channel biochemistry / quantitative in vivo subunit stoichiometry
      (e.g. calibrated fluorescence or single-molecule counting) per neuron and
      per ciliary subcompartment.
    provenance:
    - reference_id: PMID:23886944
      supporting_text: >-
        whether these mechanisms act in a protein- and cell-specific manner is
        largely unknown
    - reference_id: PMID:10064800
      supporting_text: >-
        most of the native channels in C. elegans are likely to be
        hetero-oligomers of TAX-4 and TAX-2 subunits
  - gap_statement: >-
      Which channel form (the ~25-fold more cGMP-sensitive TAX-4 homomer versus
      the less-sensitive TAX-4/TAX-2 heteromer) operates in which neuron in vivo,
      and how the TAX-2 beta subunit tunes ligand sensitivity and selectivity in
      the physiological setting, is unresolved.
    boundary: >-
      In heterologous cells the heteromer is 25-fold less cGMP-sensitive than the
      TAX-4 homomer yet remains cGMP-selective, and the two forms differ in
      divalent-cation block and single-channel behavior; the in vivo deployment of
      these forms is not mapped.
    gap_kind:
    - BIOLOGY
    dark_aspect: RESIDUAL_SUBGAP
    status: OPEN
    significance: >-
      The homomer/heteromer choice would set each neuron's cGMP operating range
      and thus its stimulus threshold and dynamic range.
    resolution: >-
      Cell-specific electrophysiology / in vivo cGMP dose-response comparisons in
      tax-2 wild-type versus mutant backgrounds.
    provenance:
    - reference_id: PMID:10064800
      supporting_text: >-
        The heteromeric TAX-4/TAX-2 channel is 25-fold less sensitive to cGMP than
        the TAX-4 channel, but it remains highly selective for cGMP over cAMP.
  - gap_statement: >-
      Whether TAX-4's in vitro cAMP responsiveness is ever used physiologically,
      and what sets the in vivo cGMP-versus-cAMP ligand tuning of the native
      channel, is unknown.
    boundary: >-
      TAX-4 is gated by cGMP and also by cAMP in heterologous assays but is
      strongly cGMP-selective; all characterized worm sensory pathways using TAX-4
      signal through cGMP produced by receptor/soluble guanylyl cyclases.
    gap_kind:
    - BIOLOGY
    dark_aspect: RESIDUAL_SUBGAP
    status: OPEN
    significance: >-
      A physiological cAMP-gated mode would expand the signaling repertoire of
      TAX-4-expressing neurons beyond cGMP transduction.
    resolution: >-
      In vivo manipulation of cAMP versus cGMP in TAX-4-expressing neurons with
      cell-specific functional imaging.
    provenance:
    - reference_id: PMID:10064800
      supporting_text: >-
        it remains highly selective for cGMP over cAMP.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:10064800
  title: Functional reconstitution of a heteromeric cyclic nucleotide-gated channel
    of Caenorhabditis elegans in cultured cells.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Establishes TAX-4 as the alpha (pore-forming) subunit and
      TAX-2 as a modifying beta subunit, that TAX-2 cannot form a channel alone,
      and that the heteromer is ~25-fold less cGMP-sensitive than the TAX-4
      homomer but stays cGMP-selective. Directly grounds the core molecular
      function and the stoichiometry/gating knowledge gaps.
- id: PMID:11879652
  title: Negative regulation and gain control of sensory neurons by the C. elegans
    calcineurin TAX-6.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Primarily a study of the TAX-6 calcineurin gain-control pathway; tax-4
      appears as a sensory-transduction component in thermosensory and olfactory
      contexts. Supports the thermosensory/olfactory behavior annotations. Cached
      abstract-only.
- id: PMID:14711416
  title: The CMK-1 CaMKI and the TAX-4 Cyclic nucleotide-gated channel regulate thermosensory
    neuron gene expression and function in C. elegans.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Directly assays TAX-4 in AFD; shows TAX-4 activity is required to maintain
      AFD-specific gene expression, morphology and function. Grounds the
      thermosensory core role and the indirect gene-expression/morphology
      non-core annotations.
- id: PMID:15220933
  title: Oxygen sensation and social feeding mediated by a C. elegans guanylate cyclase
    homologue.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Explicitly names the sensory cGMP-gated channel tax-2/tax-4 as required for
      high-O2 avoidance, together with the sGC gcy-35. Solid support for the O2 /
      aerotaxis / hyperoxia non-core annotations.
- id: PMID:15530424
  title: A new putative cyclic nucleotide-gated channel gene, cng-3, is critical for
    thermotolerance in Caenorhabditis elegans.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Focused on the cng-3 CNG channel; tax-4 is background/comparator. Supports
      only the peripheral positive-regulation-of-growth-rate IGI annotation.
      Cached abstract-only.
- id: PMID:19323996
  title: Neurons detect increases and decreases in oxygen levels using distinct guanylate
    cyclases.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Characterizes URX/BAG O2-sensing via distinct soluble guanylate cyclases;
      the cGMP signal is transduced by CNG channels including TAX-4. Supports the
      response-to-oxygen-levels non-core annotation.
- id: PMID:20436480
  title: C. elegans phototransduction requires a G protein-dependent cGMP pathway
    and a taste receptor homolog.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes a G-protein/cGMP phototransduction cascade in ASJ that opens
      cGMP-sensitive CNG channels; supports the phototransduction and
      GPCR-cGMP-second-messenger non-core annotations.
- id: PMID:21315599
  title: Regulation of response properties and operating range of the AFD thermosensory
    neurons by cGMP signaling.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text states tax-4 CNG-channel mutations abolish AFD thermosensitivity
      and isothermal tracking. Support for the thermosensory core role (the paper
      centers on the upstream gcy receptor guanylyl cyclases).
- id: PMID:21435556
  title: Temperature, oxygen, and salt-sensing neurons in C. elegans are carbon dioxide
    sensors that control avoidance behavior.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Shows CO2-evoked Ca2+ responses in AFD and BAG require cGMP-gated channels,
      and CO2 avoidance requires channels containing the TAX-2 and TAX-4 subunits.
      Grounds the CO2/chemotaxis non-core annotations and corroborates the
      abstract-only PMID:24240097.
- id: PMID:23886944
  title: Cell- and subunit-specific mechanisms of CNG channel ciliary trafficking
    and localization in C. elegans.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Defines cis-sequences and trans-factors for ciliary targeting of the TAX-4
      CNGA and TAX-2 CNGB subunits, and reports heterogeneous, cell- and
      subunit-specific channel composition across the cilium. Grounds ciliary
      localization and the in vivo stoichiometry/composition knowledge gap.
- id: PMID:23940325
  title: In vivo genetic dissection of O2-evoked cGMP dynamics in a Caenorhabditis
    elegans gas sensor.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      In vivo cGMP/Ca2+ imaging showing cGMP-gated channels are required for the
      sustained Ca2+ response and participate in negative-feedback loops. Supports
      the response-to-oxygen and negative-regulation-of-rGC-signaling annotations.
- id: PMID:24240097
  title: A chemoreceptor that detects molecular carbon dioxide.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Primary focus is the GCY-9 receptor guanylyl cyclase in BAG CO2 sensing; the
      cached record is abstract-only and does not itself mention tax-4. The tax-4
      requirement for CO2-evoked responses is independently supported
      (PMID:21435556), so the IMP CO2/Ca2+/detection annotations are retained
      (non-core) rather than removed.
- id: PMID:25303524
  title: Chemosensation of bacterial secondary metabolites modulates neuroendocrine
    signaling and behavior of C. elegans.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      ASJ chemosensory detection of P. aeruginosa metabolites induces DAF-7/TGF-beta
      expression; TAX-4 is the chemosensory channel upstream. Supports the
      positive-regulation-of-gene-expression non-core annotation.
- id: PMID:25335890
  title: Ciliopathy proteins establish a bipartite signaling compartment in a C. elegans
    thermosensory neuron.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Shows NPHP-2/inversin anchors the cGMP-gated ion channel within the proximal
      ciliary (inversin) compartment of AFD. Directly grounds the ciliary inversin
      compartment and non-motile cilium localizations.
- id: PMID:28099415
  title: Structure of a eukaryotic cyclic-nucleotide-gated channel.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      cryo-EM structure of the C. elegans TAX-4 channel (homotetramer) in the
      cGMP-bound open state; documents the unusual voltage-sensor-like domain with
      deficient voltage dependence (basis for removing the voltage-gated K+
      channel IEA term) and the selectivity-filter glutamate.
- id: PMID:31259686
  title: The Caenorhabditis elegans Tubby homolog dynamically modulates olfactory
    cilia membrane morphogenesis and phospholipid composition.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Study of TUB-1/Tubby regulation of olfactory cilia membrane; provides the
      ciliary subcellular-location evidence for TAX-4 cited by UniProt. Supports
      non-motile cilium localization.
- id: PMID:32483338
  title: Mechanism of ligand activation of a eukaryotic cyclic nucleotide-gated channel.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      cryo-EM of the C. elegans TAX-4 channel in cGMP-bound and unbound states;
      defines the ligand-activation mechanism and central-gate residues.
      Grounds the cGMP-binding core function and the gating knowledge gap.
- id: PMID:8893027
  title: Mutations in a cyclic nucleotide-gated channel lead to abnormal thermosensation
    and chemosensation in C. elegans.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Foundational paper: tax-4 mutants fail thermo- and chemosensory behaviors;
      TAX-4 is homologous to vertebrate CNG channels and functions as a CNG channel
      in cultured cells; TAX-4::GFP localizes to sensory endings. Anchors the core
      molecular function, localization and sensory-behavior annotations.
- id: PMID:9486798
  title: 'A cyclic nucleotide-gated channel inhibits sensory axon outgrowth in larval
    and adult Caenorhabditis elegans: a distinct pathway for maintenance of sensory
    axon structure.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Shows tax-2/tax-4 are required to maintain correct sensory axon structure
      (late-larval/adult axon-outgrowth phenotype). Supports the non-core
      regulation-of-axon-extension annotation.
suggested_questions:
- question: >-
    What is the endogenous TAX-4:TAX-2 subunit stoichiometry of the native sensory
    channel, and does it differ between neuron types or between ciliary
    subcompartments within a single neuron?
- question: >-
    Which neurons rely on the highly cGMP-sensitive TAX-4 homomer versus the
    less-sensitive TAX-4/TAX-2 heteromer, and how does that choice set each cell's
    stimulus threshold and dynamic range?
suggested_experiments:
- description: >-
    Quantitative in vivo measurement of TAX-4 and TAX-2 subunit copy number /
    ratio in defined sensory cilia (e.g. calibrated fluorescence or single-molecule
    counting) combined with cell-specific cGMP dose-response electrophysiology in
    tax-2(+) versus tax-2(-) backgrounds, to map homomeric versus heteromeric
    channels onto neurons and quantify how TAX-2 tunes cGMP sensitivity in situ.