Selective inflammatory pain insensitivity in the African naked mole-rat (Heterocephalus glaber).
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Naked mole-rat nociceptors respond vigorously to capsaicin, and cultured DRG neurons show Ca2+ responses to 10 nM and 2 uM capsaicin equal in incidence and magnitude to mouse neurons, so the species' behavioural insensitivity to capsaicin is not a TRPV1 defect.
"The results of these experiments indicated that the incidence and magnitude of the capsaicin responses to both low (10 nM) and high (2 μM) capsaicin concentrations are equivalent to that found in the mouse"
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TRPV1-expressing sensory fibres are synaptically connected to both superficial and deep dorsal horn neurons in the naked mole-rat, unlike the mouse, which is one explanation for the absent nocifensive response.
"Thus, TRPV1-responsive sensory fibers are synaptically connected to both superficial and deep dorsal horn neurons in the naked mole-rat."
The molecular basis of acid insensitivity in the African naked mole-rat.
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Naked mole-rat acid sensors, including TRPV1, are similar to those of other vertebrates; acid insensitivity is instead caused by a species-specific NaV1.7 variant that is potently blocked by protons.
"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"
Hypofunctional TrkA Accounts for the Absence of Pain Sensitization in the African Naked Mole-Rat.
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Naked mole-rats have fully functional TRPV1 channels; the cloned naked mole-rat protein expressed in Trpv1-null mouse sensory neurons produces heat-gated currents with a 44.4 degree C threshold and ruthenium-red-sensitive pH-gated currents, and rescues both capsaicin and heat sensitivity.
"Transfected Trpv1−/− sensory neurons had heat-gated currents with an activation threshold of 44.4°C ± 0.7°C (n = 5) and pH-gated currents sensitive to ruthenium red"
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The single naked-mole-rat-specific substitution at a conserved PKC-epsilon phospho-acceptor (Ser502 in rat numbering) is functionally silent: the T502S revertant is sensitised by PMA just as the wild-type naked mole-rat protein is.
"We also generated a naked mole-rat TRPV1T502S mutant that was also sensitized by PMA in naked mole-rat fibroblast cell lines"
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NGF fails to sensitise TRPV1 in naked mole-rat nociceptors, but the defect lies in the hypofunctional naked mole-rat TrkA receptor, not in TRPV1, which is sensitised normally in a mouse cellular context.
"in naked mole-rat IB4-negative sensory neurons, NGF never sensitized TRPV1 currents"
Independent evolution of pain insensitivity in African mole-rats: origins and mechanisms.
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Analysis of naked mole-rat TRPV1 demonstrated normal heat, pH, voltage and capsaicin sensitivity, so loss of TRPV1 function cannot explain the absence of NGF-induced thermal hyperalgesia.
"Indeed, subsequent analysis of naked mole-rat TRPV1 demonstrated that it has normal heat, pH, voltage and capsaicin sensitivity"
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Altered central connectivity of TRPV1-positive nociceptors, which contact deep as well as superficial dorsal horn neurons, is the leading explanation for why capsaicin produces no nocifensive response in this species.
"This altered connectivity of TRPV1-positive nociceptors potentially explains why capsaicin elicits a robust nocifensive response in mice, but none in the naked mole-rat."
Acid and inflammatory sensitisation of naked mole-rat colonic afferent nerves.
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Naked mole-rat TRPV1 is expressed in sensory afferents and shows proton sensitivity similar to mouse TRPV1; the species' acid insensitivity is attributed to the NaV1.7 variant rather than to any acid sensor.
"NMR TRPV1 is also expressed in sensory afferents and shows similar proton sensitivity to mouse TRPV1"
The naked mole-rat has a functional purinergic pain pathway despite having a non-functional peptidergic pain pathway.
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The behavioural insensitivity of the naked mole-rat to capsaicin is attributable to a lack of neuropeptides in its C-fibres, which makes the TRPV1 pain pathway non-functional for pain signalling while leaving the channel itself intact.
"Experiments involving immunohistochemistry and intrathecal administration of SP showed that the behavioral insensitivity to capsaicin is attributable to a lack of neuropeptides in C-fibers of the naked mole-rat"
Naked mole-rats lack cold sensitivity before and after nerve injury.
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TRPV1 is functional in the naked mole-rat and expressed at normal levels in DRG, and TRPV1 mRNA punctae per cell are statistically indistinguishable between naked mole-rat and mouse, in contrast to the TRPM8 and TRPA1 differences the paper reports.
"We also probed for TRPV1 mRNA transcripts as a further TRP channel comparison and found that the average number of punctae per cell was similar between the species"
The naked truth: a comprehensive clarification and classification of current 'myths' in naked mole-rat biology.
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The claim that naked mole-rats feel no pain has no basis in the literature: the animals respond normally to noxious heat and mechanical stimuli and lack responses only to specific stimuli such as acid and capsaicin.
"Normal nocifensive responses were reported for noxious heat and mechanical stimuli."
Artemin sensitises mouse (Mus musculus) and naked mole-rat (Heterocephalus glaber) sensory neurons in vitro.
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Capsaicin-evoked TRPV1 currents are recorded under voltage clamp from naked mole-rat DRG neurons, about 28% of which are TRPV1-positive, and artemin sensitises those neurons and reduces TRPV1 desensitisation, showing that the channel is subject to normal sensitisation by at least one growth-factor pathway.
"In summary, employing in vitro methods, we observed that artemin sensitizes both the intrinsic electrical properties of mouse and NMR DRG sensory neurons as well as sensitivity to capsaicin"
Absence of histamine-induced itch in the African naked mole-rat and "rescue" by Substance P.
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Calcium imaging of naked mole-rat DRG neurons identifies a capsaicin-responsive population (10% activated by 1 uM capsaicin alone, a further 13% by both capsaicin and histamine), confirming functional TRPV1 in small-diameter neurons.
"10% (n = 35/343) were activated by 1 μM capsaicin"
Functional neurokinin and NMDA receptor activity in an animal naturally lacking substance P: the naked mole-rat.
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Capsaicin sensitises heat-evoked foot withdrawal in mice but not in naked mole-rats, and intrathecal substance P restores heat sensitisation, locating the deficit in spinal neuropeptide signalling rather than in the capsaicin receptor.
"Capsaicin sensitizes heat-evoked foot withdrawal to heat in mice, but not naked mole-rats."
UniProt record G9DCX1 for naked mole rat Trpv1
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The 840-residue TrEMBL entry derives from mRNA JF912492 (AEV53346.1) submitted with PMID:22174253, carries six Phobius-predicted transmembrane helices, a Pfam PF00520 ion transport domain (437-695) and ankyrin repeats, and is classified in PANTHER PTHR10582:SF17.
"Multi-pass membrane protein"
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The only subcellular location on the record is an ARBA-derived keyword assignment to dendritic spine membrane, with no experimental evidence tag.
"SUBCELLULAR LOCATION: Cell projection, dendritic spine membrane"
Affinage mechanistic annotation for TRPV1 (human ortholog record)
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Conserved-mechanism baseline for the TRPV1 family: cryo-EM gating trajectory, the capsaicin binding pose and its coupling to the S4-S5 linker, PIP2 as a positive cofactor, PKA/AKAP150 and PKC-mediated sensitisation, TRPV1-TRPA1 and TRPV1-TRPV4 heteromers, and a non-channel role in modulating mu-opioid receptor desensitisation.
Gene Ontology annotation through association of InterPro records with GO terms
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
TreeGrafter-generated GO annotations
Combined Automated Annotation using Multiple IEA Methods