Hypofunctional TrkA Accounts for the Absence of Pain Sensitization in the African Naked Mole-Rat.
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The naked mole-rat TrkA kinase domain carries one to three amino acid substitutions, including a leucine-to-cysteine change at position 774 unique to this species, that render the receptor less efficient at engaging downstream signal transduction.
"Between one- and three-amino-acid substitutions in the kinase domain of the naked mole-rat TrkA are sufficient to render the receptor hypofunctional, and this is associated with the absence of heat hyperalgesia."
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The deficit is quantitative and surmountable: naked mole-rat TrkA reaches rat-equivalent TRPV1 sensitisation at 1,000 ng/mL NGF.
"When oocytes were stimulated with 1,000 ng/mL NGF, activation of the naked mole-rat TrkA receptor produced a degree of sensitization similar to that observed with rat TrkA"
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Naked mole-rat TrkA signalling remains sufficient for embryonic sensory neuron survival and development.
"It thus appears that the signaling capacity of the naked mole-rat TrkA is sufficient to support the survival and functional development of sensory neurons during embryonic development"
Selective inflammatory pain insensitivity in the African naked mole-rat (Heterocephalus glaber).
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NGF fails to produce heat hyperalgesia in naked mole-rats, acutely and chronically.
"But NGF also failed to produce heat hyperalgesia both acutely (<4 h) and chronically (>24h)"
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Naked mole-rat sensory neurons carry functional NGF receptors: TrkA-positive cultured neurons elaborate extensive neurites in response to 500 ng/mL NGF.
"In the presence of 500 ng/ml of NGF, sensory neurons elaborated extensive neurites and the same cells were positive for the trk A receptor"
Independent evolution of pain insensitivity in African mole-rats: origins and mechanisms.
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Chimeric receptor experiments localise the naked mole-rat TrkA signalling deficit to the intracellular domain.
"Indeed experiments using naked mole-rat TrkA and a chimeric TrkA (extracellular rat/intracellular naked mole-rat) further showed that activation of the naked mole-rat TrkA receptor is much less efficient at producing NGF-induced TRPV1 sensitization, thus indicating that the deficit lies in the intracellular domain"
Artemin sensitises mouse (Mus musculus) and naked mole-rat (Heterocephalus glaber) sensory neurons in vitro.
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TrkA expression and IB4 binding define largely distinct sensory neuron populations in naked mole-rat dorsal root ganglia, as in mouse.
"IB4 binding and TrkA expression also define largely distinct populations in NMR DRG neurons"
The naked mole-rat has a functional purinergic pain pathway despite having a non-functional peptidergic pain pathway.
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The P2X3 purinergic pathway is functional in naked mole-rats, showing that the species' pain-pathway deficits are selective rather than global.
"we used Ca2+-imaging of cultured dorsal root ganglion neurons and in vivo behavioral testing to demonstrate that the P2X3 pathway is functional in naked mole-rats"
UniProtKB record for Heterocephalus glaber Ntrk1 (A0AAX6QC09)
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TrEMBL entry, 798 aa, PE 3 (inferred from homology), assigned EC 2.7.10.1 and placed in the protein kinase superfamily, Tyr protein kinase family, insulin receptor subfamily. NTRK1 identity is established by InterPro IPR020461 and PANTHER PTHR24416:SF370.
"DR PANTHER; PTHR24416:SF370; HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR; 1."
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Domain architecture: signal peptide 1..33, Ig-like domain 196..285, transmembrane helix 418..441, protein kinase domain 512..783, with ATP-binding P-loop 518..526 and Lys546, proton-acceptor Asp652, and phosphotyrosine docking sites at 498 (SHC1) and 793 (PLCG1).
"FT DOMAIN 512..783"
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Subcellular location transferred by ARBA and UniProt SubCell: cell membrane, early endosome membrane, late endosome membrane and recycling endosome membrane, all as a single-pass type I membrane protein.
"SUBCELLULAR LOCATION: Cell membrane {ECO:0000256|ARBA:ARBA00004251};"
Affinage mechanistic annotation for NTRK1 (human)
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
Electronic Gene Ontology annotations created by transferring manual GO annotations between related proteins based on shared sequence features
Electronic Gene Ontology annotations created by ARBA machine learning models
TreeGrafter-generated GO annotations
Combined Automated Annotation using Multiple IEA Methods