SCN9A encodes the pore-forming alpha subunit of Nav1.7, a tetrodotoxin-sensitive voltage-gated sodium channel. It is a single large polypeptide (~1977 aa) with the canonical Nav architecture of four internal homologous repeats (domains I-IV), each containing six transmembrane segments (S1-S6); the S4 segments are the voltage sensors and the S5-S6 re-entrant loops form the Na+-selective pore. The channel is functional on its own as a multi-pass plasma membrane protein and is modulated by auxiliary beta subunits (SCN1B, SCN2B, SCN3B, SCN4B). On membrane depolarization the channel opens and selectively conducts Na+ down its electrochemical gradient, mediating the rising (depolarizing) phase of the action potential. Nav1.7 is strongly expressed in peripheral sensory neurons, most notably small-diameter nociceptive dorsal root ganglion neurons, and in sympathetic ganglion neurons; in nociceptors it localizes to the soma membrane, axons, axon/nerve terminals, and nodes of Ranvier, where it acts as a threshold/amplifier channel that boosts subthreshold depolarizations and sets the gain for action potential firing. Loss-of-function mutations cause complete congenital inability to perceive pain, while gain-of-function mutations cause inherited erythromelalgia and paroxysmal extreme pain disorder, establishing Nav1.7 as an essential, non-redundant determinant of human pain sensation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001518 voltage-gated sodium channel complex | IBA GO_REF:0000033 | ACCEPT | Summary: Nav1.7 is the pore-forming alpha subunit of a voltage-gated sodium channel that assembles with auxiliary beta subunits (SCN1B-SCN4B) into the channel complex. Membership in the VGSC complex is directly demonstrated by cryo-EM (PMID:30765606) and is consistent across the phylogenetic family. Reason: Well-supported by phylogenetic inference and corroborated by direct structural evidence; correct cellular component for the alpha subunit. Supporting Evidence: PMID:30765606 Here we report the cryo-electron microscopy structures of the human Nav1.7-Ξ²1-Ξ²2 complex |
| GO:0005248 voltage-gated sodium channel activity | IBA GO_REF:0000033 | ACCEPT | Summary: Voltage-gated sodium channel activity is the defining molecular function of Nav1.7, demonstrated directly by functional expression (PMID:7720699, PMID:17145499) and broadly conserved across the Nav family. Reason: Core molecular function, supported by both IBA and multiple experimental IDA annotations. Supporting Evidence: PMID:7720699 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. |
| GO:0035725 sodium ion transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: As a Na+-selective channel, Nav1.7 mediates transmembrane movement of Na+ ions (Na(+)(in) = Na(+)(out)), the process directly underlying its channel activity. Reason: Accurate and specific process term for a sodium channel; directly tied to the enabling molecular function and supported by the catalytic activity (Rhea:RHEA:34963). Supporting Evidence: PMID:7720699 A member of a new subclass of the voltage-activated sodium channel genes has been cloned from the human medullary thyroid carcinoma (hMTC) cell line. |
| GO:0086002 cardiac muscle cell action potential involved in contraction | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: This cardiac process term is over-propagated from the Nav family tree. Nav1.7 is not a cardiac channel; the cardiac voltage-gated sodium channel is Nav1.5 (SCN5A). The original cloning study explicitly failed to detect SCN9A transcripts in heart. Reason: Phylogenetic over-propagation. Nav1.7 is expressed in peripheral sensory and sympathetic neurons, not in cardiomyocytes, and has no established role in cardiac muscle contraction. The IBA WITH/FROM set (P35498 Nav1.1, Q14524 Nav1.5) reflects cardiac-channel paralogs, not SCN9A. Supporting Evidence: PMID:7720699 Transcripts were not identified in pituitary gland, brain, heart, liver or kidney, indicating that the hNE-Na is a sodium channel solely expressed in neuroendocrine cells. |
| GO:0001508 action potential | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Nav1.7 contributes to action potential generation, but this is a high-level parent of the more specific experimentally-supported terms neuronal action potential (GO:0019228) and membrane depolarization during action potential (GO:0086010) already annotated. Reason: Correct but redundant general term; the specific neuronal terms capture the biology more informatively. Supporting Evidence: PMID:7720699 Action potentials were generated in cells expressing high levels of hNE-Na. |
| GO:0001518 voltage-gated sodium channel complex | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic annotation of VGSC complex membership; redundant with the experimental IPI (PMID:30765606) and IBA annotations to the same term. Reason: Correct component, consistent with the experimentally and phylogenetically supported annotations to the identical term. |
| GO:0005216 monoatomic ion channel activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: High-level parent of the specific, experimentally-supported voltage-gated sodium channel activity (GO:0005248). Reason: Correct but uninformatively general; superseded by the specific MF term. |
| GO:0005248 voltage-gated sodium channel activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assertion of the core molecular function, redundant with the experimental IDA and IBA annotations to the same term. Reason: Correct core molecular function; consistent with experimental evidence. |
| GO:0005261 monoatomic cation channel activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: High-level parent of voltage-gated sodium channel activity (GO:0005248). Reason: Correct but uninformatively general; superseded by the specific Na+ channel MF term. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Nav1.7 is a multi-pass plasma membrane protein, directly demonstrated by multiple experimental studies. Reason: Correct and core cellular location of the channel; supported by EXP/IMP annotations and UniProt subcellular location (Cell membrane). Supporting Evidence: PMID:30765606 Here we report the cryo-electron microscopy structures of the human Nav1.7-Ξ²1-Ξ²2 complex |
| GO:0006811 monoatomic ion transport | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: High-level parent of sodium ion transport / sodium ion transmembrane transport. Reason: Correct but uninformatively general; superseded by the specific Na+ transport terms. |
| GO:0006814 sodium ion transport | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Sodium ion transport is the process mediated by this Na+-selective channel, though the more specific GO:0035725 (sodium ion transmembrane transport, IBA) is preferable. Reason: Correct but a less specific sibling/parent of the IBA-annotated sodium ion transmembrane transport term. |
| GO:0016020 membrane | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: High-level parent of plasma membrane (GO:0005886), the specific experimentally-supported location. Reason: Correct but uninformatively general; superseded by plasma membrane. |
| GO:0030424 axon | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Nav1.7 localizes to axons of nociceptor neurons, directly demonstrated in human iPSC-derived nociceptors (PMID:30795902) and consistent with the UniProt subcellular location (Cell projection, axon). Reason: Accurate location in sensory neurons; non-core relative to the channel's molecular function but a meaningful site of action. Redundant with the IDA-supported axon-related localizations. Supporting Evidence: PMID:30795902 localized at the soma membrane, axon, axon |
| GO:0043005 neuron projection | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Parent term encompassing axon/nerve terminals where Nav1.7 localizes; UniProt records Cell projection, neuron projection (PMID:30795902). Reason: Correct but a general parent of the more specific axon, axon terminus, and node of Ranvier localizations. Supporting Evidence: PMID:30795902 localized at the soma membrane, axon, axon |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: High-level parent of sodium ion transmembrane transport (GO:0035725). Reason: Correct but uninformatively general; superseded by the specific Na+ transmembrane transport term. |
| GO:0007623 circadian rhythm | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Circadian rhythm (IEA), transferred from mouse Scn9a, from a study of the determinants of mouse pain behaviour (PMID:25101983). Reason: The row is transferred from mouse Scn9a, annotated from a mutant phenotype in a study of the determinants of mouse pain behaviour (PMID:25101983), so an experimental observation lies behind it. Whatever dependence of pain behaviour on the time of testing was observed there, it would not make the Nav1.7 channel a participant in circadian rhythm, and no mechanism links the channel to the clock. The term over-reads a behavioural phenotype; only the abstract is available and the observation is not refuted, so the row is marked as an over-annotation rather than removed. |
| GO:0050965 detection of temperature stimulus involved in sensory perception of pain | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic ortholog-transfer from mouse Scn9a. Nav1.7 loss in humans produces thermal hypoesthesia and abolishes thermal/noxious pain, so a role in thermal pain signalling is biologically plausible, but Nav1.7 amplifies nociceptor excitability rather than directly transducing temperature. Reason: Plausible peripheral role consistent with CIP thermal phenotypes, but IEA-only and not a core/direct molecular function; Nav1.7 is a downstream amplifier, not the thermal sensor. Keep as a non-core process annotation. Supporting Evidence: PMID:30795902 Cold and warm detection thresholds in both the hand and the foot were reduced when compared to the normative range |
| GO:0050974 detection of mechanical stimulus involved in sensory perception | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic ortholog-transfer from mouse Scn9a. Nav1.7 contributes to mechanical pain sensitivity by amplifying nociceptor firing, but it is not the primary mechanotransducer; in CIP patients mechanical detection thresholds were normal while mechanical pain was abolished. Reason: Nav1.7 supports mechanical nociception but does not detect mechanical stimuli directly; the term overstates a direct sensory-transduction role. Retain as non-core rather than core. Supporting Evidence: PMID:30795902 Mechanical and vibration detection thresholds were normal |
| GO:0001518 voltage-gated sodium channel complex | IPI PMID:30765606 Structures of human Na(v)1.7 channel in complex with auxilia... | ACCEPT | Summary: Cryo-EM structures of human Nav1.7 in complex with auxiliary subunits (SCN1B/SCN2B) directly establish that SCN9A is part of the voltage-gated sodium channel complex. Reason: Directly experimentally demonstrated complex membership (ComplexPortal/structure-based); core cellular component. Supporting Evidence: PMID:30765606 Here we report the cryo-electron microscopy structures of the human Nav1.7-Ξ²1-Ξ²2 complex |
| GO:0086010 membrane depolarization during action potential | IDA PMID:30765606 Structures of human Na(v)1.7 channel in complex with auxilia... | ACCEPT | Summary: Nav1.7 conducts the Na+ influx that produces membrane depolarization during the rising phase of the action potential, consistent with its established channel function. Reason: Accurate and specific process directly mediated by the channel; well aligned with UniProt FUNCTION ("influx of Na(+) ions provokes membrane depolarization"). Supporting Evidence: PMID:30765606 Voltage-gated sodium channel Nav1.7 represents a promising target for pain relief. |
| GO:0005886 plasma membrane | EXP PMID:15385606 Electrophysiological properties of mutant Nav1.7 sodium chan... | ACCEPT | Summary: Experimental localization of Nav1.7 (including erythromelalgia mutants) to the cell membrane. Reason: Correct, experimentally-supported core location of the channel. Supporting Evidence: PMID:15385606 Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy. |
| GO:0005886 plasma membrane | EXP PMID:17167479 An SCN9A channelopathy causes congenital inability to experi... | ACCEPT | Summary: Functional expression of wild-type and mutant Nav1.7 in HEK293 cells demonstrating plasma-membrane Na+ currents (loss of function in CIP mutants). Reason: Correct, experimentally-supported core location. Supporting Evidence: PMID:17167479 Whole-cell voltage clamp recordings from cells co-expressing wild-type Nav1.7 with the Ξ²1Ξ²2 subunits, revealed a voltage-gated Na+ current |
| GO:0005886 plasma membrane | EXP PMID:19369487 Early- and late-onset inherited erythromelalgia: genotype-ph... | ACCEPT | Summary: Experimental characterization of inherited erythromelalgia mutants with cell-membrane localization/function. Reason: Correct, experimentally-supported core location. Supporting Evidence: PMID:19369487 Early- and late-onset inherited erythromelalgia: genotype-phenotype correlation. |
| GO:0005886 plasma membrane | EXP PMID:24311784 Inherited pain: sodium channel Nav1.7 A1632T mutation causes... | ACCEPT | Summary: Functional study of the A1632T erythromelalgia mutant with surface expression and altered fast inactivation. Reason: Correct, experimentally-supported core location. Supporting Evidence: PMID:24311784 sodium channel Nav1.7 A1632T mutation causes erythromelalgia due to a shift of fast inactivation |
| GO:0005886 plasma membrane | EXP PMID:25240195 Protein kinase C enhances human sodium channel hNav1.7 resur... | ACCEPT | Summary: Functional study showing PKC phosphorylation enhances Nav1.7 resurgent currents at the cell membrane. Reason: Correct, experimentally-supported core location. Supporting Evidence: PMID:25240195 Protein kinase C enhances human sodium channel hNav1.7 resurgent currents via a serine residue in the domain III-IV linker. |
| GO:0005886 plasma membrane | EXP PMID:26680203 Structural basis of Nav1.7 inhibition by an isoform-selectiv... | ACCEPT | Summary: Structural/functional study of Nav1.7 inhibition by a small-molecule antagonist, consistent with the channel residing in the cell membrane. Reason: Correct, experimentally-supported core location. Supporting Evidence: PMID:26680203 Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist. |
| GO:0005886 plasma membrane | EXP PMID:7720699 Structure and functional expression of a new member of the t... | ACCEPT | Summary: Original functional expression of hNE-Na (Nav1.7) producing voltage-gated Na+ currents and action potentials at the cell surface. Reason: Correct, experimentally-supported core location from the founding functional study. Supporting Evidence: PMID:7720699 The hNE-Na alpha subunit was transiently expressed in human embryonic kidney cells either alone or in combination with the human sodium channel beta 1 subunit. |
| GO:0005248 voltage-gated sodium channel activity | IDA PMID:7720699 Structure and functional expression of a new member of the t... | ACCEPT | Summary: The founding study cloned hNE-Na (Nav1.7) and demonstrated voltage-gated, TTX-sensitive Na+ channel activity with rapid activation/inactivation kinetics upon heterologous expression. Reason: Direct experimental demonstration of the core molecular function; primary evidence for GO:0005248. Supporting Evidence: PMID:7720699 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. |
| GO:0019228 neuronal action potential | IDA PMID:30795902 Defining the Functional Role of Na(V)1.7 in Human Nociceptio... | ACCEPT | Summary: In human iPSC-derived nociceptors and CIP studies, Nav1.7 is required for normal nociceptor action potential firing, defining its role in the neuronal action potential. Reason: Specific, experimentally-supported neuronal process directly reflecting Nav1.7's threshold/amplifier role in sensory neurons. Supporting Evidence: PMID:30795902 Defining the Functional Role of Na(V)1.7 in Human Nociception. |
| GO:0019233 sensory perception of pain | IMP PMID:30795902 Defining the Functional Role of Na(V)1.7 in Human Nociceptio... | ACCEPT | Summary: Loss of functional Nav1.7 in CIP participants abolishes the perception of noxious thermal and mechanical stimuli as painful, demonstrating an essential role in pain sensation. Reason: Decisive human-genetics evidence; core biological process of Nav1.7. Supporting Evidence: PMID:30795902 neither noxious temperature nor noxious mechanical stimuli were felt as painful |
| GO:0033268 node of Ranvier | IDA PMID:30795902 Defining the Functional Role of Na(V)1.7 in Human Nociceptio... | ACCEPT | Summary: CRISPR-tagged endogenous Nav1.7 localized to the great majority of nodes of Ranvier in myelinated human iPSC-nociceptor co-cultures. Reason: Directly demonstrated localization in human neurons; specific and informative cellular component. Supporting Evidence: PMID:30795902 NaV1.7 could be seen localized to >90% of nodes of Ranvier in myelinated axons |
| GO:0043679 axon terminus | IDA PMID:30795902 Defining the Functional Role of Na(V)1.7 in Human Nociceptio... | ACCEPT | Summary: Endogenous tagged Nav1.7 was enriched in terminal structures of human iPSC nociceptors, consistent with prior reports of axon-terminal localization in rodent DRG neurons. Reason: Directly demonstrated localization; specific and informative component relevant to action potential initiation/propagation at terminals. Supporting Evidence: PMID:30795902 staining revealed enrichment of NaV1.7 in terminal structures of our iPSC nociceptors |
| GO:0098870 action potential propagation | IDA PMID:17145499 SCN9A mutations in paroxysmal extreme pain disorder: allelic... | ACCEPT | Summary: PEPD gain-of-function mutations impair Nav1.7 fast inactivation, producing persistent Na+ current and hyperexcitability that alters action potential firing/propagation in sensory neurons. Reason: Consistent with Nav1.7's role in conducting/propagating depolarization; supported by an experimental electrophysiology study (full text read by curator). Supporting Evidence: PMID:17145499 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. |
| GO:0098870 action potential propagation | IDA PMID:7720699 Structure and functional expression of a new member of the t... | ACCEPT | Summary: Cells expressing high levels of hNE-Na (Nav1.7) generated action potentials, consistent with the channel's role in initiating and propagating electrical signals. Reason: Experimentally supported; the channel drives the depolarizing phase required for action potential propagation. Supporting Evidence: PMID:7720699 Action potentials were generated in cells expressing high levels of hNE-Na. |
| GO:0005515 protein binding | IPI PMID:37117223 Pain-causing stinging nettle toxins target TMEM233 to modula... | MARK AS OVER ANNOTATED | Summary: This IPI annotation records the experimentally-demonstrated interaction between Nav1.7 and TMEM233 (B4DJY2), a transmembrane protein required for nettle-toxin modulation of Nav1.7 gating. The generic "protein binding" term is uninformative and does not capture the regulatory nature of this interaction. Reason: Per curation guidelines, generic protein binding should be avoided in favour of an informative molecular function. The underlying biology is a channel-regulator/auxiliary-protein interaction (TMEM233 modulates Nav1.7 gating), but no sufficiently specific GO molecular-function term is clearly applicable; the specific interaction partner and regulatory role are better captured in notes/SUBUNIT than by this uninformative term. Supporting Evidence: PMID:37117223 Pain-causing stinging nettle toxins target TMEM233 to modulate Na(V)1.7 function. file:human/SCN9A/SCN9A-deep-research-falcon.md 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)**. |
| GO:0030424 axon | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer (from rat Pn1/O08562) of axonal localization; consistent with experimental human IDA data placing Nav1.7 in axons. Reason: Accurate location supported by stronger human evidence; non-core relative to molecular function and redundant with the IEA axon annotation. Supporting Evidence: PMID:30795902 localized at the soma membrane, axon, axon |
| GO:0005248 voltage-gated sodium channel activity | IDA PMID:17145499 SCN9A mutations in paroxysmal extreme pain disorder: allelic... | ACCEPT | Summary: Functional in vitro analysis of PEPD mutant Nav1.7 channels confirmed voltage-gated sodium channel activity (with altered fast inactivation in mutants). Reason: Direct experimental evidence for the core molecular function. Supporting Evidence: PMID:17145499 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. |
| GO:0005886 plasma membrane | IMP PMID:17145499 SCN9A mutations in paroxysmal extreme pain disorder: allelic... | ACCEPT | Summary: Functional expression of PEPD mutant channels demonstrates plasma-membrane Na+ currents, supporting cell-membrane localization. Reason: Correct, experimentally-supported core location. Supporting Evidence: PMID:17145499 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. |
| GO:0019233 sensory perception of pain | IMP PMID:17145499 SCN9A mutations in paroxysmal extreme pain disorder: allelic... | ACCEPT | Summary: Gain-of-function SCN9A mutations cause paroxysmal extreme pain disorder, directly linking Nav1.7 dysfunction to abnormal pain perception. Reason: Human-genetics (mutant-phenotype) evidence for the core pain-perception role of Nav1.7. Supporting Evidence: PMID:17145499 an inherited condition characterized by paroxysms of rectal, ocular, or submandibular pain with flushing |
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)