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 | REMOVE | Summary: Electronic ortholog-transfer annotation from mouse Scn9a (Q62205) via Ensembl Compara. There is no established role for human Nav1.7 in circadian rhythm, and this is not part of the channel's well-characterized nociceptor biology. Reason: Weakly supported ortholog-transfer (IEA) annotation with no experimental basis in human and no mechanistic link to the channel's core function. It does not appear in UniProt's curated function summary and risks implying an unsubstantiated role; better excluded than retained as non-core. |
| 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 |
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