REVIEWS The NaV1.7 sodium channel: from molecule to man Sulayman D. Dib-Hajj1,2, Yang Yang1,2, Joel A. Black1,2 and Stephen G. Waxman1,2 Abstract | The voltage-gated sodium channel NaV1.7 is preferentially expressed in peripheral somatic and visceral sensory neurons, olfactory sensory neurons and sympathetic ganglion neurons. NaV1.7 accumulates at nerve fibre endings and amplifies small subthreshold depolarizations, poising it to act as a threshold channel that regulates excitability. Genetic and functional studies have added to the evidence that NaV1.7 is a major contributor to pain signalling in humans, and homology modelling based on crystal structures of ion channels suggests an atomic-level structural basis for the altered gating of mutant NaV1.7 that causes pain. Neuropathic pain Voltage-gated sodium channels are essential for electro- that are not seen when these channels are expressed in 11 Pain resulting from lesions or genesis in excitable cells. Nine pore-forming α‑subunits HEK 293 cells . Methods are now available that allow the diseases of the somatosensory of such channels (referred to as channels hereinafter), expression and functional profiling of sodium channels in system. 1 NaV1.1–NaV1.9, have been identified in mammals . peripheral neurons, which more closely mimic the in vivo These isoforms share a common overall structural environment of such channels12. motif (FIG. 1). They are each composed of a long poly- In humans, gain‑of‑function mutations in SCN9A, neuropathic pain peptide (1,700–2,000 amino acids) that folds into four which encodes NaV1.7, lead to severe , homologous domains (DI–DIV) that are linked by three whereas loss‑of‑function mutations in this gene lead to loops (L1–L3), with each domain having six transmem- an indifference to pain13. Studies involving animal injury brane segments (S1–S6)2. The recent determination models and functional studies of neuronal excitability fol- of the crystal structure of the homotetrameric bacte- lowing expression of human mutant NaV1.7 have provided rial sodium channel3 has provided insights into the mechanistic insights into the role of this channel in the atomic structure of mammalian sodium channels and pathophysiology of pain. Additional studies have linked 14,15 the interactions between the voltage-sensing domain NaV1.7 to other sensory modalities, including olfaction , (VSD; encompassing S1–S4) and the pore module (PM; the afferent limb of the cough reflex16 and acid sensing17. S5–S6) within each of the four homologous domains. In this Review, we discuss functional and modelling Genetic, structural and functional studies have shown studies of NaV1.7 that have yielded new insights into the that Nav1.7 regulates sensory neuron excitability and is structure–function relationship of gating mechanisms in a major contributor to several sensory modalities, and this channel and its contribution to neuronal responses 1Department of Neurology, have established the contribution of this sodium channel under normal and pathological conditions. We also and Center for Neuroscience isoform to human pain disorders (FIG. 1). explore strategies for targeting Na 1.7 in the treatment and Regeneration Research, V Yale University School of The nine sodium channel isoforms display different of pain and, finally, identify unanswered questions 1 Medicine, New Haven, kinetics and voltage-dependent properties . Their differ- regarding the role of NaV1.7 in pain signalling. Connecticut 06510, USA. ential deployment in different types of neurons endows 2Rehabilitation Research these cells with distinct firing properties. Sodium chan- Cellular and subcellular distribution Center, Veterans Affairs Connecticut Healthcare nels associate with multiple protein partners that regulate Three sodium channels — NaV1.7, NaV1.8 and NaV1.9 4–7 System, West Haven, channel trafficking and gating , allowing sodium chan- — are preferentially expressed in peripheral neurons. Connecticut 06516, USA. nel properties to be modulated in a cell-type-specific NaV1.7 expression was first detected in somatosensory Correspondence to S.G.W. manner (for examples, see REFS 8–10), highlighting the and sympathetic ganglion neurons18, and has since e‑mail: stephen.waxman@ need to study these channels within their native neu- been reported in myenteric neurons19, olfactory sen- yale.edu 14,15 16,20 doi:10.1038/nrn3404 ronal background whenever practicable. For example, sory neurons (OSNs) , visceral sensory neurons 21–23 Published online the pathogenic G616R variant of NaV1.7 displays gating and smooth myocytes . NaV1.7 is expressed in both 12 December 2012 abnormalities within dorsal root ganglion (DRG) neurons large and small diameter DRG neurons (FIG. 2), including NATURE REVIEWS | NEUROSCIENCE VOLUME 14 | JANUARY 2013 | 49 © 2013 Macmillan Publishers Limited. All rights reserved REVIEWS a DI DII DIII DIV VSD PM S3 S5 S2 S4 S1 S6 7 3 10 6 7 2 4 8 8 16 2 15 5 17 19 4 11 14 2 18 1 5 6 1213 6 3 5 6 7 9 10 C 4 1 1 L1 3 L2 L3 9 N 1 b VSD 1 Q10R 2 I136V 3 S211P 4 F216S 5 I234T 1 7 6 S241T 7 N395K 8 V400M 9 G616R 10 L823R DI PM DIV 4 3 6 11 I848T 12 G856D* 13 L858H 14 L858F 15 A863P 2 16 16 V872G 17 ΔL955 18 P1308L 19 F1449V 8 6 5 8 2 1 R996C 2 V1298F 3 V1298D 4 V1299F 5 I1461T 15 9 13 14 7 10 6 F1462V 7 T1464I 8 G1607R 9 M1627K 10 A1632E‡ 12 17 19 4 3 D623N 4 I720K 5 I739V 11 1 R185H 2 I228M 2 3 6 M932L/V991L 7 M1532I 10 18 DII DIII 5 1 § 4 R1150W Figure 1 | Domain structure of NaV1.7 and locations of characterized mutations inNature NaV1.7‑related Reviews | Neurosciencepain disorders. a | The sodium channel α‑subunit is a long polypeptide that folds into four homologous domains (DI–DIV), each of which consists of six transmembrane segments (S1–S6). The four domains are joined by three loops (L1‑L3). Within each domain, S1–S4 comprise the voltage-sensing domain (VSD; S4, depicted in green, characteristically contains positively charged arginine and lysine residues), and S5–S6 and their extracellular linker comprise the pore module (PM). The linear schematic of the full-length channel shows the locations of amino acids affected by the gain‑of‑function SCN9A mutations that are linked to inherited erythromelalgia (IEM; red symbols), paroxysmal extreme pain disorder (PEPD; grey symbols), and small-fibre neuropathy (SFN; yellow symbols). b | View of the folded NaV1.7 from the intracellular side of the membrane based on the recently determined crystal structure of a bacterial sodium channel3. The structure shows the central ion-conducting PM and four peripheral VSDs. Conformational changes in the VSDs in response to membrane depolarization are transmitted to the PMs through the S4–S5 linkers (identified by arrows through the helices). Mutations that seem distant from each other on the linear model can in fact be in close proximity to each other in the more biologically relevant folded structure. *The patient with this mutation showed symptoms common to IEM and SFN. ‡The patient carrying this mutation showed symptoms and channel properties common to both IEM and PEPD. §This substitution is encoded by a polymorphism that was present in approximately 30% of ethnically matched Caucasian individuals of European descent in a control population81. Part a is modified, with permission, from REF. 37 © (2007) Elsevier Science. 50 | JANUARY 2013 | VOLUME 14 www.nature.com/reviews/neuro © 2013 Macmillan Publishers Limited. All rights reserved REVIEWS Roles in multiple sensory modalities Box 1 | NaV1.7 contributes most of the sodium current in OSNs Pain. As stated above, NaV1.7 is expressed in both large Na 1.7 is the predominant sodium channel in olfactory sensory neurons (OSNs)14,15. 13 V and small diameter DRG neurons , including 85% of 2+ – Although an elaborate Ca -based and Cl -based signalling amplification system in the functionally identified nociceptors24. These observations, OSN cilia can boost odorant receptor potential133,134, the abundant expression of Na 1.7 V together with its properties as a threshold channel, sug- in these cells14,15 and the ability of Na 1.7 to boost weak depolarizations, support a role V gested that Na 1.7 contributes to pain signalling. The for this sodium channel in the initiation of action potential firing along the peripheral V olfactory neuraxis. Mouse and rat OSNs produce a tetrodotoxin (TTX)-sensitive recent discovery of gain‑of‑function SCN9A mutations 14,15,135 in human pain disorders solidified the status of Na 1.7 as current that is consistent with the predominant expression of NaV1.7 in these V cells. Interestingly, the hyperpolarized activation and inactivation properties of this having a central role in pain signalling13, and its involve- TTX-sensitive current are different from those recorded from NaV1.7 expressed in HEK ment in pathological pain signalling is discussed below. 293 cells33,136 or dorsal root ganglion (DRG) neurons11,35, and those in native rat DRG 137–139 14 neurons . Ahn et al. reported identical sequences of the NaV1.7 cDNA in mouse Olfaction. The initial discovery that global knockout of OSN and DRG neuron samples. Together, these data suggest that post-translational Scn9a in mice is neonatally lethal, probably because the modulation of Na 1.7 or interaction with OSN-specific channel partners may lead to 43 V newborn mice do not feed , and the subsequent discov- altered gating properties of Na 1.7 in OSNs compared with DRG neurons. V ery that humans with homozygous SCN9A-null muta- 44,45 tions are anosmic suggested that NaV1.7 is important in olfaction. Nassar et al.43 noted the absence of milk in 24 –/– functionally identified Aβ-fibres and C‑fibres .