Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy.
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Erythromelalgia (PERYTHM) gain-of-function mutations shift Nav1.7 activation to more hyperpolarized potentials, supporting cell-membrane localization and a role in nociceptor hyperexcitability.
"Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy."
SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes.
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PEPD is caused by SCN9A gain-of-function missense mutations that reduce Nav1.7 fast inactivation, producing persistent sodium current and linking the channel to a heritable pain disorder.
"Functional analysis in vitro of three of these mutant Na(v)1.7 channels revealed a reduction in fast inactivation, leading to persistent sodium current."
An SCN9A channelopathy causes congenital inability to experience pain.
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Biallelic SCN9A nonsense mutations (S459X, I767X, W897X) cause complete loss of Nav1.7 function and congenital inability to perceive pain, with all other sensory modalities preserved.
"Our data suggest that SCN9A is an essential and non-redundant requirement for nociception in humans."
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Nav1.7 is the alpha-subunit of a TTX-sensitive voltage-gated sodium channel strongly expressed in nociceptive DRG neurons.
"encoding the alpha-subunit of the voltage-gated sodium channel, Na(v)1.7, which is strongly expressed in nociceptive neurons"
Early- and late-onset inherited erythromelalgia: genotype-phenotype correlation.
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Inherited erythromelalgia gain-of-function Nav1.7 mutations correlate with age of onset, supporting cell-membrane localization and the channel's role in pain.
"Early- and late-onset inherited erythromelalgia: genotype-phenotype correlation."
Inherited pain: sodium channel Nav1.7 A1632T mutation causes erythromelalgia due to a shift of fast inactivation.
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The A1632T erythromelalgia mutation alters Nav1.7 fast inactivation, a gain-of-function mechanism, with the channel expressed at the cell membrane.
"sodium channel Nav1.7 A1632T mutation causes erythromelalgia due to a shift of fast inactivation"
Protein kinase C enhances human sodium channel hNav1.7 resurgent currents via a serine residue in the domain III-IV linker.
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PKC phosphorylation at Ser-1490 in the domain III-IV linker enhances Nav1.7 resurgent sodium currents, modulating the membrane-resident channel.
"Protein kinase C enhances human sodium channel hNav1.7 resurgent currents via a serine residue in the domain III-IV linker."
Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist.
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Crystallographic study of a Nav1.7 voltage-sensor domain bound by an isoform-selective antagonist, consistent with the channel as a membrane-embedded drug target.
"Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist."
Structures of human Na(v)1.7 channel in complex with auxiliary subunits and animal toxins.
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Cryo-EM structures show human Nav1.7 alpha subunit assembled with auxiliary beta subunits (SCN1B/SCN2B) into the voltage-gated sodium channel complex, a multi-pass membrane protein.
"Here we report the cryo-electron microscopy structures of the human Nav1.7-β1-β2 complex"
Defining the Functional Role of Na(V)1.7 in Human Nociception.
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In CIP participants with biallelic loss-of-function SCN9A mutations, noxious thermal and mechanical stimuli are not perceived as painful, while mechanical/vibration detection thresholds remain normal.
"neither noxious temperature nor noxious mechanical stimuli were felt as painful"
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CRISPR-tagged endogenous Nav1.7 localizes to the soma membrane, axons, axon terminals, and >90% of nodes of Ranvier in human iPSC-derived nociceptors.
"NaV1.7 could be seen localized to >90% of nodes of Ranvier in myelinated axons"
Pain-causing stinging nettle toxins target TMEM233 to modulate Na(V)1.7 function.
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Nav1.7 interacts with the transmembrane protein TMEM233 (B4DJY2), which modulates channel gating; this is the basis of the GO:0005515 protein binding annotation.
"Pain-causing stinging nettle toxins target TMEM233 to modulate Na(V)1.7 function."
Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells.
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hNE-Na (Nav1.7) is a 1977-aa TTX-sensitive voltage-activated sodium channel; heterologous expression yields rapidly activating/inactivating Na+ currents and generates action potentials.
"The channel exhibited rapid activation and inactivation kinetics, and was blocked by tetrodotoxin and cadmium with IC50 values of 24.5 nM and 1.1 mM, respectively."
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SCN9A transcripts are not detectable in heart, indicating Nav1.7 is not a cardiac sodium channel.
"Transcripts were not identified in pituitary gland, brain, heart, liver or kidney"
Falcon deep research report for human SCN9A
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Falcon deep research affirms the core molecular function as a voltage-gated Na+ channel selective for Na+ via the canonical DEKA selectivity filter (Asp-Glu-Lys-Ala across DI-DIV), supporting the GO:0005248 / GO:0005261 annotations.
"NaV1.7 is selective for Na+ and shares the canonical NaV architecture and **DEKA selectivity filter** (Asp-Glu-Lys-Ala across DI-DIV) described for eukaryotic NaV alpha subunits."
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Falcon deep research frames Nav1.7 as a nociceptor "threshold channel" enriched at the plasma membrane of DRG, trigeminal and sympathetic ganglion neurons, consistent with the sensory-perception-of-pain and plasma-membrane annotations.
"NaV1.7 is a **plasma-membrane** channel enriched in **nociceptive neurons**, with high expression reported in **dorsal root ganglia (DRG)**, **trigeminal ganglia**, and **sympathetic ganglia**."
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Falcon deep research corroborates that TMEM233 (a dispanin-family protein) is an essential Nav1.7-interacting accessory protein, supporting the regulatory interpretation of the GO:0005515 (TMEM233) annotation rather than generic protein binding.
"identified **TMEM233 (a dispanin-family protein)** as an essential **NaV1.7-interacting accessory protein** for the action of the plant-derived knottin toxin **Excelsatoxin A (ExTxA)**."
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Falcon deep research highlights regulation of Nav1.7 surface density by NEDD4L-mediated ubiquitination of a C-terminal PY motif - a trafficking/turnover regulatory axis (consistent with the UniProt NEDD4/NEDD4L SUBUNIT note) that is not captured by any current GOA annotation.
"the E3 ligase **NEDD4L ubiquitinates the cytoplasmic C-terminus of NaV1.7** ... **post-translational modification and trafficking/turnover regulation** are likely important determinants of NaV1.7 surface density and nociceptor excitability."