SCN9A (Nav1.7) review notes

UniProt: Q15858 | HGNC: SCN9A | Taxon: NCBITaxon:9606 (human)
PANTHER family: PTHR10037 (VOLTAGE-GATED CATION CHANNEL CALCIUM AND SODIUM)

Core biology (synthesis)

SCN9A encodes the pore-forming alpha subunit of Nav1.7, a tetrodotoxin-sensitive
voltage-gated sodium channel. It is a single-polypeptide channel of ~1977 aa with the
canonical Nav architecture: 4 internal homologous repeats (domains I–IV), each with 6
transmembrane segments (S1–S6); 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 but
is modulated by beta subunits (SCN1B/SCN2B/SCN3B/SCN4B).

• Molecular function: voltage-gated sodium channel activity — opens on membrane
  depolarization and selectively conducts Na+ down its electrochemical gradient, mediating
  the rising (depolarizing) phase of the action potential.
  [Rhea:RHEA:34963 Na(+)(in)=Na(+)(out); PMID:7720699 functional expression, TTX-sensitive,
  rapid activation/inactivation kinetics]
• Cellular location: plasma membrane, multi-pass; in nociceptor neurons localizes to
  axons, neuron terminals, and nodes of Ranvier. PMID:30795902
• Biological role: Nav1.7 is the principal sodium channel setting the gain/threshold of
  nociceptor (pain-sensing) neurons, strongly expressed in dorsal root ganglion (DRG)
  and sympathetic ganglia. It acts as a "threshold channel" that amplifies subthreshold
  depolarizations.

Tissue specificity

Strongly expressed in dorsal root ganglion (nociceptors), sympathetic neurons, with
minor levels elsewhere (smooth muscle, MTC cell line, C-cell carcinoma, vagus nerve).
Original cloning paper explicitly: "Transcripts were not identified in pituitary gland,
brain, heart, liver or kidney" — i.e. NOT a cardiac channel (cardiac Nav is
Nav1.5/SCN5A). PMID:7720699

Human genetics = strongest functional evidence

Nav1.7 function is exceptionally well validated by human Mendelian genetics:
- Congenital insensitivity to pain (CIP) — autosomal recessive, biallelic nonsense/LOF
mutations (S459X, I767X, W897X); complete loss of function abolishes pain. "SCN9A is an
essential and non-redundant requirement for nociception in humans." PMID:17167479
- Inherited/primary erythromelalgia (PERYTHM) — gain-of-function (hyperpolarizing shift
of activation) → burning extremity pain. [PMID:15385606, PMID:19369487, PMID:24311784]
- Paroxysmal extreme pain disorder (PEPD) — gain-of-function (impaired fast
inactivation → persistent current). PMID:17145499

These establish GO:0019233 sensory perception of pain (IMP) on the firmest possible footing.

Annotation-relevant publication notes

• PMID:7720699 (EMBO J 1995): cloning/functional expression of hNE-Na (=Nav1.7). Supports
  VGSC activity (IDA), plasma membrane, action potential generation/propagation. Full text
  abstract-only in cache but classic primary functional paper.
• PMID:17145499 (Neuron 2006, PEPD): supports VGSC activity (IDA), plasma membrane (IMP),
  sensory perception of pain (IMP), action potential propagation.
• PMID:30795902 (Neuron 2019, "Defining Functional Role of Nav1.7 in Human Nociception"):
  full text available; supports neuronal action potential (IDA), sensory perception of pain
  (IMP), node of Ranvier (IDA), axon terminus (IDA).
• PMID:30765606 (Science 2019, cryo-EM Nav1.7-beta1-beta2 + toxins): supports VGSC complex
  (part_of, ComplexPortal IPI), membrane depolarization during action potential (IDA).
• PMID:37117223 (Nat Commun 2023, nettle toxins/TMEM233): IPI to TMEM233 (B4DJY2) modulating
  Nav1.7 gating. Annotated as generic GO:0005515 protein binding — per project guidelines
  "protein binding" is uninformative; the real biology is channel-regulator interaction.

Questionable / over-propagated annotations to scrutinize

1. GO:0086002 cardiac muscle cell action potential involved in contraction (IBA,
   GO_REF:0000033). Nav1.7 is NOT a cardiac channel (that is Nav1.5/SCN5A). This is
   phylogenetic over-propagation from the Nav family tree. → MARK_AS_OVER_ANNOTATED / NON_CORE.
2. GO:0007623 circadian rhythm (IEA, Ensembl ortholog GO_REF:0000107, from mouse
   Q62205/Scn9a). Not a recognized core function of human Nav1.7; ortholog-transfer, weak.
   → KEEP_AS_NON_CORE at best / candidate over-annotation.
3. GO:0050974 detection of mechanical stimulus involved in sensory perception (IEA,
   Ensembl). Nav1.7 is primarily a nociceptor amplifier; mechanosensation detection per se
   is debatable — Nav1.7 contributes to mechanical pain but is not the mechanotransducer.
4. GO:0050965 detection of temperature stimulus involved in sensory perception of pain
   (IEA, Ensembl). Plausible (Nav1.7 needed for some thermal/cold pain) but IEA-only.
5. Generic/high-level IEA terms (monoatomic ion channel activity, monoatomic cation channel
   activity, ion transport, transmembrane transport, membrane) — correct but redundant
   parents of the specific experimentally-supported terms; non-core.
6. GO:0005515 protein binding (IPI, PMID:37117223) — uninformative per guidelines.