Trpv1 encodes the naked mole-rat transient receptor potential vanilloid 1 channel (vanilloid receptor 1, VR1), an 840-residue polymodal non-selective cation channel of the TRPV family. The subunit has the canonical TRPV architecture: a large cytoplasmic N-terminal ankyrin-repeat domain, six transmembrane helices with a re-entrant pore loop between S5 and S6, and a cytoplasmic C-terminal tail; four subunits assemble around a central Ca2+-permeable pore. It resides in the plasma membrane of small-diameter dorsal root ganglion neurons and their peripheral cutaneous and central dorsal-horn terminals, where about 28% of DRG neurons are TRPV1-positive, a fraction indistinguishable from mouse. The channel is opened by noxious heat, by extracellular protons and by vanilloid agonists such as capsaicin, and the resulting cation influx raises cytosolic Ca2+ and depolarises the nociceptor. The naked mole-rat channel is functionally ordinary. Expressed in sensory neurons from Trpv1-null mice it produces capsaicin-, heat- and pH-gated currents with a heat-activation threshold of about 44 degrees C, and naked mole-rat sensory neurons respond to nanomolar capsaicin with the same incidence and magnitude as mouse neurons; its proton sensitivity matches that of mouse TRPV1. The species' well-known behavioural insensitivity to capsaicin therefore does not originate in the channel: it is explained downstream, by the absence of substance P and CGRP from cutaneous C-fibres and by an unusual pattern of TRPV1-fibre termination in both superficial and deep laminae of the dorsal horn, and behavioural responsiveness to capsaicin is restored by intrathecal substance P. Likewise, the absence of NGF- and capsaicin-induced thermal hyperalgesia in this species reflects a hypofunctional TrkA receptor rather than a defect in TRPV1, which is sensitised normally when placed in a mouse cellular context and is sensitised by artemin in naked mole-rat neurons. One naked-mole-rat-specific substitution is documented, a threonine at the position corresponding to Ser502 of rat TRPV1 (a PKC-epsilon phospho-acceptor), but it is functionally silent for sensitisation. Naked mole-rat acid insensitivity is likewise unrelated to this channel, arising instead from a proton-blocked variant of the voltage-gated sodium channel NaV1.7.
Definition: Enables the transmembrane transfer of a cation by a channel that opens when a vanilloid ligand, such as capsaicin or resiniferatoxin, is bound in a pocket formed by the transmembrane domain and accessible from the inner leaflet of the plasma membrane.
Justification: GO has no term for vanilloid or capsaicin gating, so the defining pharmacological property of TRPV1 - the one that names the protein (vanilloid receptor 1) and the one that has been measured most often in the naked mole rat - can only be recorded with the generic GO:0099094 ligand-gated monoatomic cation channel activity. GO:0005230 (extracellular ligand-gated) would be wrong, because the vanilloid pocket is reached from the cytoplasmic leaflet rather than from the extracellular face. A dedicated child of GO:0099094 would let curators distinguish vanilloid-sensitive TRPV channels from vanilloid-insensitive ones (avian TRPV1, TRPV2) without resorting to free text.
Parent term: ligand-gated monoatomic cation channel activity
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005216 monoatomic ion channel activity | IEA GO_REF:0000120 | MODIFY | Summary: Correct but uninformatively general. Naked mole-rat TRPV1 is not merely an ion channel: its gating has been measured directly, and it is a polymodal channel opened by noxious heat, by protons and by vanilloid ligands. Because the specific gating modes are experimentally established for this species' protein, the generic parent term should give way to the informative children. Reason: The cloned naked mole-rat cDNA (the very accession annotated here, EMBL AEV53346.1 from PMID:22174253) was expressed in sensory neurons from Trpv1-null mice and shown to produce heat-gated currents with a threshold of 44.4 +/- 0.7 degrees C and pH-gated, ruthenium-red-sensitive currents, and to restore capsaicin sensitivity [PMID:27732851]. Review of that work records normal heat, pH, voltage and capsaicin sensitivity [PMID:32206859]. GO:0005216 discards all of this. Replace with GO:0097604 (temperature-gated cation channel activity), which captures the heat gating, and GO:0099094 (ligand-gated monoatomic cation channel activity), which captures vanilloid gating. The cation-level terms are used in preference to their ion-level parents GO:0097603 and GO:0015276 because TRPV1 is a non-selective cation channel, so the cation restriction is part of what has been measured rather than an assumption. GO:0099094 is preferred over GO:0005230 (extracellular ligand-gated) because capsaicin engages a vanilloid pocket reached from the inner leaflet rather than an extracellular binding site. Ca2+ selectivity is separately and correctly captured by GO:0005262 below. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: temperature-gated cation channel activity ligand-gated monoatomic cation channel activity Supporting Evidence: PMID:27732851 Transfected Trpv1β/β sensory neurons had heat-gated currents with an activation threshold of 44.4Β°C Β± 0.7Β°C (n = 5) and pH-gated currents sensitive to ruthenium red PMID:27732851 the naked mole-rat TRPV1 protein can rescue capsaicin and heat sensitivity in Trpv1β/β sensory neurons PMID:32206859 Indeed, subsequent analysis of naked mole-rat TRPV1 demonstrated that it has normal heat, pH, voltage and capsaicin sensitivity |
| GO:0005262 calcium channel activity | IEA GO_REF:0000120 | ACCEPT | Summary: Core molecular function, and positively confirmed in naked mole-rat material rather than merely projected. Capsaicin evokes Ca2+ influx in naked mole-rat DRG neurons at the same incidence and magnitude as in mouse, and the cloned naked mole-rat protein produces capsaicin-evoked Ca2+ signals when expressed in naked mole-rat fibroblasts. Reason: Fura-2 calcium imaging of cultured naked mole-rat DRG neurons showed capsaicin-evoked Ca2+ responses equivalent to mouse at both 10 nM and 2 uM capsaicin, with no difference in the proportion of responding neurons [PMID:18232734]. Capsaicin-evoked Ca2+ signals were also recorded from a naked mole-rat fibroblast line transfected with nmrTrpv1 [PMID:27732851], establishing that the Ca2+ conductance is a property of this protein and not of some other channel in the neuron. The ARBA/PANTHER projection is therefore not merely plausible but directly corroborated for this species. Propagation Review Root cause: NO FAILURE CORE Supporting Evidence: PMID:18232734 The results of these experiments indicated that the incidence and magnitude of the capsaicin responses to both low (10 nM) and high (2 ΞΌM) capsaicin concentrations are equivalent to that found in the mouse PMID:18232734 No significant differences were observed in the proportion of capsaicin-sensitive neurons between mouse and naked mole-rat. PMID:27732851 To measure PKCΞ΅ sensitization of nmrTRPV1, we used a new naked mole-rat fibroblast cell line |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Correct and directly supported. Naked mole-rat TRPV1 carries current across the surface membrane of sensory neurons and mediates Ca2+ entry from the extracellular medium, both of which require plasma-membrane residence. Reason: Capsaicin applied to the bath evokes whole-cell inward currents in naked mole-rat DRG neurons under voltage clamp [PMID:40705105] and Ca2+ influx from the extracellular solution in fura-2 imaging [PMID:18232734]; TRPV1-immunoreactive fibres and varicosities are present at central terminals in the dorsal horn and are functionally presynaptic there [PMID:18232734]. The protein is also reported to be expressed at normal levels in naked mole-rat DRG [PMID:32880221]. This is the informative cellular component for the gene. Propagation Review Root cause: NO FAILURE CORE Supporting Evidence: PMID:40705105 In the same recordings, TRPV1 function was assessed in voltage clamp configuration by applying 1 Β΅M capsaicin PMID:18232734 We thus used cultures of naked mole-rat DRG neurons and applied low concentrations of capsaicin onto single cells and measured receptor activation using fura-2 PMID:32880221 the TRPV1 receptor is expressed at normal levels in DRG and functions despite a lack of behavioral response to capsaicin |
| GO:0006811 monoatomic ion transport | IEA GO_REF:0000002 | ACCEPT | Summary: A generic InterPro2GO process term derived from the ion-transport (Pfam PF00520) domain. It is true of this protein and harmless, but it is a high-level parent; the specific and informative process annotation is GO:0098703 (calcium ion import across plasma membrane), already present in this set. Reason: The InterPro signatures that generate this term (IPR005821 ion transport domain, IPR008347 TrpV1-4, IPR024862 TRPV) are all genuinely present in G9DCX1, and the protein does conduct ions: capsaicin evokes inward currents and Ca2+ entry in naked mole-rat sensory neurons [PMID:18232734, PMID:40705105]. Broader than the evidence warrants, but not wrong, and the appropriate treatment of a correct-but-general IEA parent is to retain it rather than churn it. Propagation Review Root cause: NO FAILURE NON CORE Supporting Evidence: PMID:18232734 In contrast, nociceptors do respond vigorously to capsaicin, and we also show that sensory neurons express a transient receptor potential vanilloid channel-1 ion channel that is capsaicin sensitive. |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: Correct but the least informative of the three cellular-component rows. TRPV1 is a multi-pass membrane protein with six predicted transmembrane helices in this record; the specific location is the plasma membrane (GO:0005886, also annotated here). Reason: G9DCX1 has six Phobius-predicted transmembrane helices (residues 436-455, 475-493, 514-534, 540-559, 580-602, 659-683) and a Pfam PF00520 ion-transport domain spanning 437-695, so membrane residence is not in doubt. Retained as a true parent of GO:0005886 rather than modified, since the informative child is already asserted independently in this annotation set. Propagation Review Root cause: NO FAILURE NON CORE Supporting Evidence: file:HETGA/Trpv1/Trpv1-uniprot.txt Multi-pass membrane protein |
| GO:0032591 dendritic spine membrane | IEA GO_REF:0000044 | MARK AS OVER ANNOTATED | Summary: An over-annotation. This is a UniProt subcellular-location keyword transfer (UniProtKB-SubCell SL-0285, reached via ARBA00004332) that asserts a specific CNS postsynaptic compartment. It is IEA-only in every well-curated mammalian ortholog, so what propagates here is an unvalidated keyword artefact rather than an experimental finding, and every naked mole-rat observation of this protein is in peripheral sensory neurons. Reason: Three positive reasons, not merely "this was transferred electronically". First, the provenance: the UniProt record carries the location only with an ARBA evidence tag and no experimental support. Second, the term is IEA in human (Q8NER1), mouse (Q704Y3) and rat (O35433) alike, whereas the genuinely experimental CNS locations on those orthologs are postsynaptic membrane (GO:0045211, IDA/IMP in mouse and rat) and dendrite (GO:0030425, IDA in rat) - so even in the source species the spine-specific term is unvalidated. Third, all naked mole-rat data on this protein concern DRG somata, cutaneous C-fibre endings and central terminals in the dorsal horn [PMID:18232734, PMID:40705105, PMID:32880221]; no naked mole-rat study has examined TRPV1 in brain, let alone at dendritic spines. REMOVE is not used because TRPV1 does have real postsynaptic and dendritic localisation in rodent CNS, so the term is unsupported and over-specific for this species rather than false for the family. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: COMPARTMENT OR COMPLEX MISMATCH SOURCE EVIDENCE WEAK Supporting Evidence: file:HETGA/Trpv1/Trpv1-uniprot.txt SUBCELLULAR LOCATION: Cell projection, dendritic spine membrane PMID:18232734 Thus, TRPV1-responsive sensory fibers are synaptically connected to both superficial and deep dorsal horn neurons in the naked mole-rat. |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | ACCEPT | Summary: Generic InterPro2GO process term from the ion-transport domain signature IPR005821. True of this protein, but a high-level parent; the specific process is calcium ion import across the plasma membrane. Reason: Naked mole-rat TRPV1 moves cations across the plasma membrane when gated by capsaicin, heat or protons [PMID:27732851, PMID:40705105]. The term is correct at a coarse level and carries the domain-based inference honestly; it is retained rather than modified because GO:0098703 in this same set already supplies the informative child. Propagation Review Root cause: NO FAILURE NON CORE Supporting Evidence: PMID:27732851 The cloned naked mole-rat TRPV1 receptor (nmrTrpv1) displays biophysical properties similar to its mouse counterpart with respect to proton, capsaicin, and heat gating |
| GO:0098703 calcium ion import across plasma membrane | IEA GO_REF:0000118 | ACCEPT | Summary: The most informative process term in the set, and correctly placed. The TreeGrafter node PTN000061681 propagates the TRPV1 ancestral function of admitting Ca2+ from the extracellular space into the cytosol, and this is exactly what has been measured for the naked mole-rat protein. Reason: Capsaicin application to naked mole-rat DRG neurons produces a rise in intracellular Ca2+ measured by fura-2 ratiometric imaging, of the same incidence and magnitude as in mouse [PMID:18232734], and the same Ca2+ response is seen for the cloned protein in naked mole-rat fibroblasts [PMID:27732851]. Whole-cell voltage-clamp recordings confirm that the capsaicin-evoked conductance is present in naked mole-rat neurons [PMID:40705105]. The phylogenetic placement of the node is not in question here: the naked mole rat sits squarely inside the TRPV1 clade, and there is target-specific experimental confirmation rather than any evidence of loss or divergence. Propagation Review Root cause: NO FAILURE CORE Supporting Evidence: PMID:18232734 The results of these experiments indicated that the incidence and magnitude of the capsaicin responses to both low (10 nM) and high (2 ΞΌM) capsaicin concentrations are equivalent to that found in the mouse PMID:40705105 In the same recordings, TRPV1 function was assessed in voltage clamp configuration by applying 1 Β΅M capsaicin PMID:32880221 The receptor for capsaicin, TRPV1, is functional in the NMR |
| GO:0034605 cellular response to heat | IDA PMID:27732851 Hypofunctional TrkA Accounts for the Absence of Pain Sensiti... | NEW | Summary: Missing from the seeded set. Naked mole-rat TRPV1 is a heat-activated channel with a normal noxious-heat threshold, demonstrated by expressing the cloned naked mole-rat protein in sensory neurons that lack their own TRPV1. Reason: Heat-gated currents with an activation threshold of 44.4 +/- 0.7 degrees C were recorded from Trpv1-null mouse sensory neurons transfected with naked mole-rat Trpv1, a cell background in which heat-activated currents are otherwise rare, and the naked mole-rat protein rescued heat as well as capsaicin sensitivity [PMID:27732851]. Review of that work confirms normal heat sensitivity for this ortholog [PMID:32206859]. This is a cellular-level response term and is safely supported; it is deliberately narrower than the organism-level pain terms carried by the mouse and human orthologs, which are not proposed here. Supporting Evidence: PMID:27732851 Transfected Trpv1β/β sensory neurons had heat-gated currents with an activation threshold of 44.4Β°C Β± 0.7Β°C (n = 5) and pH-gated currents sensitive to ruthenium red PMID:27732851 the naked mole-rat TRPV1 protein can rescue capsaicin and heat sensitivity in Trpv1β/β sensory neurons PMID:32206859 Indeed, subsequent analysis of naked mole-rat TRPV1 demonstrated that it has normal heat, pH, voltage and capsaicin sensitivity |
| GO:0071468 cellular response to acidic pH | IDA PMID:27732851 Hypofunctional TrkA Accounts for the Absence of Pain Sensiti... | NEW | Summary: Missing from the seeded set, and an unusually informative annotation for this species. Naked mole-rat TRPV1 retains normal proton gating even though the animal is famously insensitive to acid, because acid insensitivity is a NaV1.7 phenotype rather than a TRPV1 phenotype. Reason: pH-gated, ruthenium-red-sensitive currents were recorded from Trpv1-null mouse sensory neurons expressing the naked mole-rat protein [PMID:27732851]. Direct comparison of cloned acid-sensitive proteins found naked mole-rat TRPV1 to have proton sensitivity similar to the mouse orthologue [PMID:32206859], as did the original characterisation [PMID:22174253], and this is restated in the colonic-afferent literature [PMID:31992138]. Recording this term makes explicit a result that is easy to lose: the naked mole rat's acid insensitivity does not run through TRPV1. Supporting Evidence: PMID:27732851 Transfected Trpv1β/β sensory neurons had heat-gated currents with an activation threshold of 44.4Β°C Β± 0.7Β°C (n = 5) and pH-gated currents sensitive to ruthenium red PMID:32206859 When examining the proton sensitivity of cloned acid-sensitive proteins, naked mole-rat TRPV1, ASIC1a and ASIC1b have a similar proton sensitivity to their mouse orthologues PMID:22174253 acid sensors (acid-sensing ion channels and the transient receptor potential vanilloid-1 ion channel) in naked mole-rat nociceptors are similar to those in other vertebrates PMID:31992138 NMR TRPV1 is also expressed in sensory afferents and shows similar proton sensitivity to mouse TRPV1 |
| GO:0071312 cellular response to alkaloid | IDA PMID:18232734 Selective inflammatory pain insensitivity in the African nak... | NEW | Summary: Missing from the seeded set. Capsaicin is a plant alkaloid, and the cellular response of naked mole-rat sensory neurons to it - Ca2+ influx and inward current - is one of the best-documented facts about this protein. The corresponding term is curated on the human, mouse and rat orthologs. Reason: Nanomolar capsaicin evokes Ca2+ responses in cultured naked mole-rat DRG neurons at the same incidence and magnitude as in mouse [PMID:18232734, PMID:20497578], and 1 uM capsaicin evokes whole-cell inward currents under voltage clamp [PMID:40705105]. This is a cellular response term and is agnostic about the animal's behaviour: the naked mole rat shows no nocifensive response to capsaicin, but that is a spinal wiring and neuropeptide phenotype, not a failure of the cellular response [PMID:32206859, PMID:32478202]. Supporting Evidence: PMID:18232734 In contrast, nociceptors do respond vigorously to capsaicin, and we also show that sensory neurons express a transient receptor potential vanilloid channel-1 ion channel that is capsaicin sensitive. PMID:20497578 10% (n = 35/343) were activated by 1 ΞΌM capsaicin PMID:40705105 In the same recordings, TRPV1 function was assessed in voltage clamp configuration by applying 1 Β΅M capsaicin |
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Download this section (compressed HTML)Q: Does naked mole-rat TRPV1 mediate the species' normal nocifensive response to noxious heat? Noxious-heat withdrawal is normal in this species and TRPV1 is expressed at normal levels, but in mice C-fibre noxious-heat sensitivity survives Trpv1 deletion, so the organism-level term GO:0050965 cannot be transferred on expression data alone.
Suggested experts: Gary R. Lewin, Ewan St. John Smith, Thomas J. Park
Q: Is naked mole-rat TRPV1 expressed anywhere outside the somatosensory system - brain, bladder urothelium, gut epithelium, vasculature - where mouse and rat TRPV1 carry organ-physiology annotations such as temperature homeostasis, regulation of urine volume and regulation of systemic arterial blood pressure?
Suggested experts: Ewan St. John Smith
Q: Does naked mole-rat TRPV1 form heteromeric channels with TRPA1 or TRPV4, and does its calmodulin, ATP and PIP2 regulation match that of the mouse and rat channels? None of these has been tested in this species, yet all are carried as keyword or ISS annotations on the orthologs.
Q: Beyond the functionally silent Ser502Thr (rat numbering; Thr505 in G9DCX1), does the naked mole-rat TRPV1 sequence carry any substitution that alters desensitisation or tachyphylaxis? Artemin was found to diminish capsaicin-evoked desensitisation in naked mole-rat neurons, which raises the question of whether baseline desensitisation kinetics differ from mouse.
Suggested experts: Ewan St. John Smith
Experiment: Test whether pharmacological block of TRPV1 (a selective antagonist such as AMG9810 or BCTC, applied topically or intraplantar) raises radiant-heat and hot-plate withdrawal latencies in naked mole-rats, using mice as a positive control and confirming target engagement by loss of capsaicin-evoked currents in ex vivo skin-nerve recordings from the same animals. A negative result would show that, as in Trpv1-null mice, noxious-heat transduction in naked mole-rat C-fibres is carried by another transducer, and would justify leaving GO:0050965 off this gene.
Hypothesis: Naked mole-rat TRPV1 is required for normal nocifensive responses to noxious heat in this species, despite contributing nothing to capsaicin-evoked pain behaviour.
Type: pharmacological behavioural assay with electrophysiological confirmation
Experiment: Express nmrTrpv1 and mouse Trpv1 in parallel in HEK293 cells or Xenopus oocytes and measure, on the same rigs and days, capsaicin dose-response (EC50), proton dose-response, heat-activation threshold and Q10, single-channel conductance and Ca2+ permeability ratio (PCa/PNa). The published comparisons are qualitative ("similar", "indistinguishable") and are the sole basis for accepting several of the projected molecular-function annotations; a quantitative side-by-side would either convert those to firm evidence or reveal a quantitative divergence that the qualitative statements hide.
Hypothesis: Naked mole-rat TRPV1 has the same polymodal gating parameters as mouse TRPV1 when both are recorded side by side in the same expression system.
Type: comparative heterologous electrophysiology
Experiment: Perform RNAscope for Trpv1 mRNA plus validated immunohistochemistry across naked mole-rat hippocampus, cortex, hypothalamus, bladder, colon and mesenteric vessels, with DRG as a positive control and Trpv1-null mouse tissue as an antibody specificity control. This would directly resolve the GO:0032591 dendritic spine membrane annotation, which is currently a keyword transfer with no experimental support in any species.
Hypothesis: Naked mole-rat TRPV1 protein is confined to the somatosensory system and is absent from the CNS compartments (dendritic spines, postsynaptic membrane) that the UniProt keyword annotation asserts.
Type: in situ hybridisation and immunohistochemistry survey
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