Tac1 encodes protachykinin-1 (PPT), the secreted precursor of the tachykinin neuropeptides substance P and neurokinin A. A cleaved signal peptide directs the 130-residue preproprotein into the secretory pathway, where prohormone convertases cut at paired basic residues and a donor glycine is converted into the C-terminal amide that neurokinin receptors require for potency. The naked mole-rat precursor has the beta-preprotachykinin architecture: substance P (RPKPQQFFGLM, residues 58-68) and neurokinin A (HKTDSFVGLM, residues 98-107) occupy the same positions as in the human protein, both mature peptides are identical in sequence to their human counterparts, and both amidation and dibasic cleavage sites are conserved. Once released, substance P acts on the neurokinin-1 receptor (TACR1) and neurokinin A on the neurokinin-2 receptor (TACR2); both are Gq-coupled, so agonist binding drives phospholipase C activation, inositol trisphosphate production and a rise in cytosolic calcium in the target cell. Through these receptors tachykinins excite neurons, contract smooth muscle, dilate blood vessels, and relay nociceptive and pruritic signals from primary afferents onto second-order neurons in the superficial dorsal horn. In the naked mole-rat the peptide has a distinctive anatomical distribution: substance P and CGRP immunoreactivity are absent from cutaneous C-fibre nociceptors and from small-diameter dorsal root and trigeminal ganglion somata, while peptidergic fibres persist in visceral afferents, and the gene is transcribed in the hypothalamus among other tissues. The neurokinin-1 receptor remains present and pharmacologically normal in the superficial dorsal horn of this species, so introducing substance P intrathecally, or re-expressing preprotachykinin in its sensory neurons, restores capsaicin-evoked nocifensive behaviour, thermal hyperalgesia and histamine-induced scratching. This regional restriction of where the peptide is made, rather than any change to the protein itself, underlies the animal's selective insensitivity to inflammatory pain and to pruritogens.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: Protachykinin-1 is a secreted preproprotein: it carries a cleaved N-terminal signal peptide and is processed to tachykinins that act on cell-surface neurokinin receptors on other cells, so both the precursor and its products are extracellular. Reason: This is the least contentious row in the set and nothing about the naked mole rat bears on it. The keyword mapping (UniProtKB-SubCell:SL-0243, Secreted) is corroborated independently within the same record by a SignalP-predicted signal peptide at residues 1-19, and by the biology of the mature products: substance P and neurokinin A are agonists of cell-surface GPCRs and must be released to act. The human ortholog P20366 carries GO:0005576 with experimental (EXP) evidence as well as a PAINT IBA. Retained as core, because being secreted is part of what this gene product is for, not an incidental location. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0243 · Secreted SUPPORTS TRANSFER Keyword itself is ARBA-derived for this entry, but is independently corroborated by the SignalP signal peptide in the same record. Supporting Evidence: file:HETGA/Tac1/Tac1-uniprot.txt SUBCELLULAR LOCATION: Secreted file:HETGA/Tac1/Tac1-bioinformatics/RESULTS.md only `SIGNAL 1..19`, `CHAIN 20..130`, and two SMART `Tachykinin` domain calls at `58..68` and `97..107` |
| GO:0006954 inflammatory response | IEA GO_REF:0000118 | KEEP AS NON CORE | Summary: Tachykinins are canonical mediators of neurogenic inflammation in mammals, and the naked mole rat retains the capability - intrathecal substance P enhances its formalin response. But the principal route by which substance P drives inflammation in other mammals, release from peptidergic cutaneous C-fibre terminals, is precisely the arm documented to be hypofunctional in this species. Reason: This is the one row where the naked-mole-rat literature legitimately changes the curation call, and it changes it to non-core rather than to REMOVE. Two facts pull in opposite directions and both must be respected. On one side, the peptidergic inflammatory arm is explicitly described as hypofunctional in this species, and the animal shows selective insensitivity to inflammatory pain (PMID:18232734); a blanket involved_in inflammatory response transferred from a PANTHER node founded on mouse and human data therefore overstates what this protein routinely does in the intact naked mole rat. On the other side, the capability is demonstrably retained, not lost: adding substance P back enhances the formalin-induced response, which is exactly what would not happen if the annotation were wrong. There is also no evidence either way about the visceral or immune substance P pool, where the peptide is present (PMID:21200438). REMOVE would assert something false about the protein; ACCEPT would present a contextual, largely latent role as a core function. Keep it, marked non-core. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: PANTHER:PTN000134172 · TreeGrafter ancestral node (PTHR11250, TACHYKININ) SUPPORTS TRANSFER Node placement is sound; the human ortholog P20366 carries GO:0006954 as a PAINT IBA. The qualification is target-specific tissue context, not a fault in the node. Supporting Evidence: PMID:32478202 naked mole-rats do not express neuropeptides, such as Substance P and calcitonin gene-related peptide in their cutaneous C-fibers, effectively making the peptidergic pain pathway hypofunctional PMID:32478202 here we showed that intrathecal SP administration enhanced the formalin-induced pain response in naked mole-rats, suggesting that activation of the peptidergic pathway is important for the full behavioral response PMID:32478202 In most mammals, TRPV1+ peptidergic C-fibers synapse in lamina I of the spinal cord where the neurokinin I receptor (NK1r) for SP is also expressed PMID:34476892 have diminished substance P signalling under hypercapnia PMID:31992138 CGRP-positive extrinsic neuronal varicosities were identified encircling and tracking with blood vessels within the mesentery supplying the distal colon of NMR |
| GO:0007217 tachykinin receptor signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: The naked mole-rat precursor encodes two peptides that literally satisfy this term's definition, and the naked mole-rat spinal cord contains a neurokinin-1 receptor that responds to substance P with the expected agonist and antagonist pharmacology. Reason: The GO definition of this term specifies a tachykinin as a short peptide with the terminal sequence Phe-X-Gly-Leu-Met-NH2. Both peptides encoded here end in exactly that motif (FFGLM at 64-68, FVGLM at 103-107), each followed by the glycine that donates the amide and by a dibasic KR convertase site, so the sequence itself satisfies the definition rather than merely resembling something that does. The pathway is then shown to be operational in this species: NK1 receptor immunoreactivity is present in superficial dorsal horn neurons, intrathecal substance P sensitises heat-evoked withdrawal, and the NK1R antagonist GR-82334 reverses that sensitisation, which the authors take as showing the receptor is normal. The tissue-restricted absence of the peptide from cutaneous fibres does not touch this annotation: GO records what a gene product does, not which cells choose to express it, and the add-back experiments confirm rather than undermine the pathway assignment. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR008215 · Tachykinin_dom SUPPORTS TRANSFER Domain match is corroborated residue-by-residue by the F-x-G-L-M check. PANTHER:PTN000134172 · TreeGrafter ancestral node (PTHR11250, TACHYKININ) SUPPORTS TRANSFER Supporting Evidence: file:HETGA/Tac1/Tac1-bioinformatics/RESULTS.md Both tachykinin cores end in the `F-x-G-L-M` consensus that the `GO:0007217` definition uses to define a tachykinin, and both are immediately followed by `G-K-R` PMID:18232734 we were able to detect the neurokinin-1 (NK1) receptor immunoreactivity in naked mole-rat superficial spinal cord neurons PMID:21200438 SP also sensitized foot withdrawal responses in naked mole-rats, an effect most clearly observed at the highest dose tested PMID:21200438 This shows that NK1 receptors function normally in the naked mole-rat file:HETGA/Tac1/Tac1-uniprot.txt Belongs to the tachykinin family. |
| GO:0031835 substance P receptor binding | IEA GO_REF:0000118 | ACCEPT | Summary: Naked mole-rat substance P is identical in sequence to human substance P, and the naked mole-rat NK1 receptor binds and responds to it: intrathecal substance P sensitises nociceptive behaviour and rescues histamine itch, and both effects are reversed by an NK1R antagonist. Reason: This is the annotation that the naked-mole-rats-lack-substance-P framing would tempt a reviewer to remove, and removing it would be wrong. The claim in the literature is about where the peptide is made, not about what it is: substance P occupies positions 58-68 of this precursor as RPKPQQFFGLM, with zero substitutions relative to human, and the flanking amidation and dibasic cleavage signals are conserved. The binding itself is then demonstrated in this species by intervention rather than inferred - exogenous substance P produces NK1R-dependent sensitisation that the antagonist GR-82334 reverses, and re-expressing preprotachykinin in naked mole-rat sensory neurons restores capsaicin-evoked thermal hyperalgesia. A cell-type-restricted loss of expression is not a change in molecular function, and GO has no slot for expression pattern on an MF annotation; encoding it as REMOVE would assert that this protein cannot engage an NK1 receptor, which the rescue experiments directly refute. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000134172 · TreeGrafter ancestral node (PTHR11250, TACHYKININ) SUPPORTS TRANSFER Human P20366 carries GO:0031835 as a PAINT IBA. The transfer is additionally confirmed target-side: the naked mole-rat substance P sequence is identical to human and its receptor is pharmacologically functional in this species. Supporting Evidence: file:HETGA/Tac1/Tac1-bioinformatics/RESULTS.md `RPKPQQFFGLM` occupies exactly positions 58-68, the same coordinates as in the reviewed human entry, with zero substitutions. PMID:20497578 following intrathecal SP administration, naked mole-rats displayed robust scratching behavior in response to histamine that was significantly greater than after intrathecal saline PMID:20497578 We propose that addition of SP activates superficially located neurons expressing neurokinin-1 receptors and thus increases the excitatory drive into the superficial laminae PMID:18232734 We used a neurotropic virus to reintroduce PPT gene expression into naked mole-rat sensory neurons and found that capsaicin could now induce thermal hyperalgesia in the treated mole-rats PMID:21200438 These results indicate that spinal neurons in naked mole-rats have functional SP and NMDA receptors, but that these receptors do not participate in heat-evoked foot withdrawal unless SP is experimentally introduced file:HETGA/Tac1/Tac1-deep-research-falcon.md In the naked mole-rat, the coding locus is apparently intact, but SP expression is selectively absent from cutaneous peptidergic C-fibers. file:HETGA/Tac1/Tac1-deep-research-falcon.md This should not be generalized to complete organism-wide absence: SP- and CGRP-positive presumptive sensory fibers have been reported in visceral tissues, suggesting tissue- or neuronal-subtype-specific regulation PMID:32880221 NMRs also lack calcitonin gene-related peptide (CGRP) and substance P in nociceptive C fibers |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Correct, and well grounded upstream: substance P binding to Gq-coupled NK1 receptors activates phospholipase C and releases calcium via IP3, and the human ortholog from which this row was projected carries the same term with direct-assay evidence. It is nonetheless a generic downstream readout rather than a distinguishing function. Reason: No doubt about correctness is intended by this action. The row is an Ensembl Compara projection from human TAC1 (UniProtKB:P20366 / ENSP00000321106) together with the PANTHER node, and checking the human record shows GO:0007204 there carries an IDA (PMID:8957234) as well as a PAINT IBA, so the source is experimentally grounded rather than inferred-only. The mechanism is also the one the naked mole-rat authors themselves invoke to explain their spinal substance P results. The reason for non-core is granularity, not doubt: raising cytosolic calcium is the effector consequence shared by essentially every Gq-coupled ligand, and what identifies this protein is the tachykinin receptor engagement captured by GO:0007217 and GO:0031835. A more informative term for the same biology, GO:0007209, is proposed below as a new annotation. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P20366 · human TAC1 (protachykinin-1) SUPPORTS TRANSFER Verified via QuickGO that P20366 carries GO:0007204 with IDA (PMID:8957234) plus a PAINT IBA, so the ortholog projection is not resting on another inference. PANTHER:PTN000134172 · TreeGrafter ancestral node (PTHR11250, TACHYKININ) SUPPORTS TRANSFER Supporting Evidence: PMID:21200438 the binding of SP to NK1 receptors, which leads to phospholipase C (PLC) activation and subsequent IP3-mediated calcium release file:HETGA/Tac1/Tac1-uniprot.txt activation of G(q) and phosphatidylinositol |
| GO:0031837 substance K receptor binding | ISS file:HETGA/Tac1/Tac1-bioinformatics/RESULTS.md | NEW | Summary: The existing annotation set covers only the substance P / NK1R arm, but this precursor also encodes neurokinin A, whose preferred receptor is the neurokinin-2 receptor TACR2 (the substance K receptor). Naked mole-rat neurokinin A is identical in sequence to human neurokinin A. Reason: A real gap rather than a refinement. GOA gives this protein GO:0031835 alone, which describes only what substance P does; nothing in the set represents the second mature peptide. Neurokinin A occupies residues 98-107 as HKTDSFVGLM, at the same coordinates as in the reviewed human entry and with zero substitutions, followed by the same Gly-amide donor and dibasic cleavage site as substance P, so the peptide is encoded and processable. UniProt's own FUNCTION statement for this entry names TACR2 explicitly as a receptor for the gene product. The sibling term GO:0031837 under GO:0031834 neurokinin receptor binding is the exact match. Flagged honestly as sequence-inferred: the entire naked mole-rat experimental literature concerns substance P and NK1R, and there is no naked mole-rat measurement of neurokinin A or of TACR2 function. Supporting Evidence: file:HETGA/Tac1/Tac1-bioinformatics/RESULTS.md **Neurokinin A is also present and also identical** (`HKTDSFVGLM`, 98-107). The naked mole-rat precursor therefore encodes *both* mature tachykinins file:HETGA/Tac1/Tac1-uniprot.txt Is a ligand for TACR2 file:HETGA/Tac1/Tac1-deep-research-falcon.md SP preferentially activates **TACR1/NK1R**, whereas NKA and its extended products preferentially activate **TACR2/NK2R**. file:HETGA/Tac1/Tac1-deep-research-falcon.md Production of NKA or extended NKA peptides is biologically plausible from mammalian conservation but should remain annotated as **predicted** until naked-mole-rat transcript isoforms and endogenous processed peptides are established by long-read RNA sequencing and targeted peptidomics. |
| GO:0007209 phospholipase C-activating tachykinin receptor signaling pathway | ISS file:HETGA/Tac1/Tac1-uniprot.txt | NEW | Summary: A more informative child of GO:0007217 that names the Gq / phospholipase C arm of neurokinin receptor signalling, and so makes the existing GO:0007204 calcium annotation mechanistically interpretable instead of leaving it as a bare readout. Reason: GOA currently pairs a general pathway term (GO:0007217) with a terminal effector term (GO:0007204) and asserts nothing about the step that connects them. GO:0007209 is that step, and it is the term the human ortholog already carries. UniProt's FUNCTION statement for this entry describes exactly this coupling, and the naked mole-rat authors invoke the same PLC / IP3 mechanism when explaining their spinal substance P results. Proposed as ISS and no stronger: the naked mole-rat statement in PMID:21200438 is a general mechanistic account citing prior work, not a measurement of phospholipase C activation in this species, and no such measurement exists. Supporting Evidence: file:HETGA/Tac1/Tac1-uniprot.txt activation of G(q) and phosphatidylinositol PMID:21200438 the binding of SP to NK1 receptors, which leads to phospholipase C (PLC) activation and subsequent IP3-mediated calcium release file:HETGA/Tac1/Tac1-deep-research-falcon.md Conserved neurokinin-receptor signaling is primarily Gq/11-linked, activating phospholipase C, IP3-dependent intracellular Ca |
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Download this section (compressed HTML)Q: Is the absence of substance P from naked mole-rat cutaneous C-fibres transcriptional - Tac1 simply not expressed in those neurons - or is the peptidergic nociceptor population itself reduced or missing? The distinction matters for how the phenotype should be represented, because only the first is compatible with a normal Tac1 gene in a normal cell type.
Suggested experts: Gary R. Lewin, Ewan St. John Smith, Thomas J. Park
Q: In which naked mole-rat tissues is mature, amidated substance P actually present, and at what concentration relative to mouse? Every existing statement rests on immunohistochemistry in skin, DRG and spinal cord; there is no quantification anywhere, including in the viscera where the peptide is reported to persist.
Suggested experts: Ewan St. John Smith, Thomas J. Park
Q: Does the naked mole rat produce neurokinin A, and is its neurokinin-2 receptor (TACR2) functional? The whole species literature concerns substance P and NK1R, yet the precursor encodes neurokinin A identically to human, so a second, entirely unexamined tachykinin arm exists.
Suggested experts: Ewan St. John Smith
Q: Which preprotachykinin splice forms (alpha, beta, gamma, delta) does the naked mole rat transcribe, and in what proportions across skin, viscera and hypothalamus? The UniProt entry declares no alternative products, so the isoform repertoire of this species is unknown.
Q: Does the naked mole rat produce CAP-TAC1, the capped (pyroglutamylated, amidated) TAC1-derived circulating peptide recently described in mouse and human plasma? If a third class of product comes from this locus and acts on tachykinin receptors from the circulation, then an animal characterised as lacking substance P in one tissue might nonetheless have a systemic tachykinin tone that nobody has looked for.
Q: Given that Tac1 is expressed in the naked mole-rat hypothalamus, do the non-nociceptive roles established for Tac1 in mouse - energy balance, reproductive timing, affective behaviour - operate normally in this species? The cutaneous phenotype has attracted all the attention, but nothing predicts that the central functions are affected.
Suggested experts: Thomas J. Park
Experiment: Single-cell or single-nucleus RNA-seq of naked mole-rat dorsal root ganglia, with matched mouse DRG processed in parallel, quantifying Tac1 alongside Calca, Trpv1, P2rx3 and IB4-binding markers. Retrograde labelling from skin versus colon before dissociation would separate the cutaneous and visceral afferent populations so that Tac1 expression can be compared between them within the same animal. This directly distinguishes the gene being switched off in these neurons from the neurons being absent.
Hypothesis: Tac1 mRNA is absent or strongly reduced specifically in naked mole-rat small-diameter cutaneous nociceptors, while being expressed at normal levels in visceral afferent and central neurons.
Type: single-cell transcriptomics with retrograde tracing
Experiment: Targeted LC-MS/MS quantification of amidated substance P and neurokinin A in naked mole-rat skin, dorsal root ganglia, spinal cord, colon and hypothalamus, using stable-isotope-labelled synthetic peptide standards and mouse tissue as the comparator. Because the naked mole-rat and human peptides are sequence-identical, existing human standards and transitions can be used unmodified. This would replace the entire immunohistochemical evidence base with quantitative measurements and would show whether the conserved amidation and dibasic sites are actually used in vivo.
Hypothesis: Naked mole-rat tissues contain mature amidated substance P and neurokinin A, at levels that are low in skin but comparable to mouse in gut and hypothalamus.
Type: targeted quantitative peptidomics
Experiment: Express naked mole-rat TACR2 and, as a control, naked mole-rat TACR1 in a heterologous cell line and measure Gq-coupled responses (IP1 accumulation and calcium mobilisation) to synthetic naked mole-rat neurokinin A and substance P across a concentration range, with the human receptor-ligand pairs run alongside. This closes the arm of the pathway that no naked mole-rat study has examined, and it tests the sequence-inferred GO:0031837 annotation proposed here rather than leaving it as a homology assertion.
Hypothesis: The naked mole-rat neurokinin-2 receptor is functional and responds to naked mole-rat neurokinin A with potency comparable to the human pair.
Type: heterologous receptor pharmacology
Experiment: Whole-mount immunohistochemistry for substance P and CGRP, with PGP9.5 as a pan-neuronal counterstain, on naked mole-rat colon, bladder and mesentery alongside skin from the same animals, using mouse tissue as a positive control and peptide pre-adsorption as the specificity control. The visceral substance P claim currently propagates through review prose citing older work, and only CGRP has been shown directly in the cached colonic study; this would supply the missing primary image for substance P itself.
Hypothesis: Peptidergic innervation persists in naked mole-rat viscera, and substance P immunoreactivity - not only CGRP - can be demonstrated there directly.
Type: comparative immunohistochemistry
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