| Category | Key points | Representative recent sources (DOI/URL) | Evidence type |
|---|---|---|---|
| Identity | Human **SCN9A** encodes **NaV1.7**; explicit match to **UniProt Q15858** in biochemical study of the full-length channel. C-terminal region includes **IQ** motif and **PY (PPSY)** motif relevant to regulation. (pqac-00000009, pqac-00000004) | **Wright et al., 2023**. DOI: 10.1021/acsbiomedchemau.3c00031; https://doi.org/10.1021/acsbiomedchemau.3c00031 | Biochemistry |
| Structure | Canonical voltage-gated sodium channel α-subunit architecture: ~2,000 aa, **4 homologous domains (DI–DIV)**, each with **6 TM helices (S1–S6)**; **S1–S4** form VSDs, **S5–S6 + P-loop** form pore/selectivity filter; **DEKA** selectivity filter. (pqac-00000001, pqac-00000005) | **Toffano et al., 2020**. DOI: 10.1038/s41598-020-74591-y; https://doi.org/10.1038/s41598-020-74591-y. **Wood et al., 2025**. DOI: 10.1085/jgp.202513778; https://doi.org/10.1085/jgp.202513778 | Structural/functional review, computational synthesis |
| Localization | NaV1.7 is highly expressed in **nociceptive neurons** of **dorsal root ganglia (DRG)**, **trigeminal ganglia**, and **sympathetic ganglia**; positioned at the plasma membrane to regulate excitability. (pqac-00000014) | **Dormer et al., 2023**. DOI: 10.2147/JPR.S388896; https://doi.org/10.2147/JPR.S388896 | Review |
| Physiology | In human iPSC-derived nociceptors from inherited erythromelalgia, SCN9A/NaV1.7 gain-of-function shifts activation to more negative voltages, lowers firing threshold, and enhances AP upstroke; supports NaV1.7 as a **threshold channel** for action-potential initiation in pain pathways. (pqac-00000011, pqac-00000015) | **Meents et al., 2019**. DOI: 10.1097/j.pain.0000000000001511; https://doi.org/10.1097/j.pain.0000000000001511 | Human electrophysiology, iPSC nociceptors |
| Regulation | NaV1.7 C-terminus is **ubiquitinated by NEDD4L**; study identified ubiquitinated lysines and defined a CT region containing an **EF-hand-like bundle**, **IQ motif**, and **PY motif** that can regulate channel trafficking/turnover. (pqac-00000004, pqac-00000009) | **Wright et al., 2023**. DOI: 10.1021/acsbiomedchemau.3c00031; https://doi.org/10.1021/acsbiomedchemau.3c00031 | Biochemistry, mass spectrometry |
| Regulation / accessory proteins | Plant toxin **ExTxA** requires **TMEM233** (a sensory-neuron dispanin) for pharmacological activity at NaV1.7; toxin-induced persistent current in human sensory neurons was largely blocked by **Pn3a 100 nM**, showing accessory-protein dependence of Nav1.7 modulation. (pqac-00000019, pqac-00000032) | **Jami et al., 2023**. DOI: 10.1038/s41467-023-37963-2; https://doi.org/10.1038/s41467-023-37963-2 | Electrophysiology, molecular pharmacology |
| Structural pharmacology | Cryo-EM structures of human NaV1.7 bound to drugs/lead compounds at **2.6–3.2 Å** mapped multiple binding sites, including **site BIG** beneath the intracellular gate; **vixotrigine** occupies a fenestration site; lacosamide also showed unexpected occupancy near the selectivity filter. Figure-level structural atlas of druggable sites was retrieved. (pqac-00000018, pqac-00000030, pqac-00000035) | **Wu et al., 2023**. DOI: 10.1038/s41467-023-38942-3; https://doi.org/10.1038/s41467-023-38942-3 | Cryo-EM structural pharmacology |
| Structural mechanism | Engineered Nav1.7 mutants solved at **2.9–3.4 Å** showed correlation between **pore-domain contraction** and right-shifted activation/static inactivation, refining structure–function understanding of gating states relevant to drug design. (pqac-00000020) | **Li et al., 2024**. DOI: 10.1073/pnas.2322899121; https://doi.org/10.1073/pnas.2322899121 | Cryo-EM, electrophysiology |
| Genetics | Human genetics strongly validate SCN9A: **gain-of-function** variants cause painful syndromes including **inherited erythromelalgia (IEM)**, **paroxysmal extreme pain disorder (PEPD)**, and some **small-fiber neuropathy (SFN)**; **loss-of-function** variants cause **congenital insensitivity to pain (CIP)**. (pqac-00000010, pqac-00000011, pqac-00000013) | **Baker & Nassar, 2020**. DOI: 10.1007/s00424-020-02419-9; https://doi.org/10.1007/s00424-020-02419-9. **Meents et al., 2019**. DOI above | Review, human genetics, electrophysiology |
| Clinical translation | Small-molecule clinical development has been active but disappointing overall; review notes **~30% of idiopathic SFN** linked to SCN9A and summarizes funapide/TV-45070, PF-05089771, vixotrigine, and lacosamide programs; expression in DRG/TG/sympathetic neurons supports target rationale but efficacy has often been modest. (pqac-00000025, pqac-00000039) | **Dormer et al., 2023**. DOI: 10.2147/JPR.S388896; https://doi.org/10.2147/JPR.S388896 | Review, clinical landscape |
| Clinical translation / registry | **PF-05089771** Phase 2 painful diabetic peripheral neuropathy study **NCT02215252**: completed; **n=141**; monotherapy **150 mg BID** and **add-on pregabalin 150 mg BID** arms; endpoints included daily pain NRS, responder rates, NPSI, PGIC, sleep interference, rescue medication. (pqac-00000044, pqac-00000045) | **ClinicalTrials.gov NCT02215252**; https://clinicaltrials.gov/study/NCT02215252 | Clinical trial registry |
| Clinical translation / precision medicine | **Lacosamide** genotype-guided SCN9A gain-of-function SFN study **NCT01911975**: randomized quadruple-masked crossover; **n=25**; **200 mg BID** vs placebo; pain assessed over **33 weeks**. (pqac-00000027, pqac-00000040) | **ClinicalTrials.gov NCT01911975**; https://clinicaltrials.gov/study/NCT01911975 | Clinical trial registry |
| Clinical translation / observational genomics | **SCN9A polymorphism** study **NCT02496455**: prospective postoperative-pain cohort after cesarean section; **n=200**; genotyped rs6746030, rs7604448, rs10930214, rs7595255; outcomes were VAS pain and **24 h tramadol** consumption. (pqac-00000043) | **ClinicalTrials.gov NCT02496455**; https://clinicaltrials.gov/study/NCT02496455 | Clinical trial registry, observational genetics |
| Emerging therapeutics | **Single-domain antibody (VHH)** against human NaV1.7 slowed deactivation, reduced nociceptor firing, and reversed hyperalgesia in rodent models, demonstrating feasibility of a biologic modality. (pqac-00000022, pqac-00000033) | **Martina et al., 2024**. DOI: 10.1002/advs.202405432; https://doi.org/10.1002/advs.202405432 | Biologic engineering, electrophysiology, animal models |
| Emerging therapeutics | **Engineered zinc-finger repressors (ZFRs)** targeting SCN9A achieved **90% repression** in human iPSC-derived neurons, **up to 70%** repression in mouse DRG, and **up to 60%** repression in nonhuman-primate DRG after AAV delivery, supporting gene-regulatory analgesic strategies. (pqac-00000026) | **Samie et al., 2024**. DOI: 10.1101/2024.09.06.609976; https://doi.org/10.1101/2024.09.06.609976 | Preclinical gene regulation, AAV, transcript repression |
| Emerging clinical precision medicine | **BHV-7000/opakalim** inherited erythromelalgia study **NCT07262268**: Phase 1b, double-blind crossover, **n=5**, enrolling participants with characterized **NaV1.7 gain-of-function SCN9A mutations**; endpoints include maximum pain intensity and attack metrics. (pqac-00000042) | **ClinicalTrials.gov NCT07262268**; https://clinicaltrials.gov/study/NCT07262268 | Clinical trial registry |


*Table: This table summarizes functional annotation, mechanism, genetics, and clinical translation for human SCN9A/Nav1.7 using the most relevant gathered evidence, prioritizing 2023–2024 sources where possible. It is useful as a compact reference linking molecular function to experimental support and translational status.*