The NaV1.7 sodium channel: from molecule to man

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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.

Key Points

  • The voltage-gated sodium channel NaV1.7 is expressed in most nociceptive dorsal root ganglion (DRG) neurons and is present peripherally within free nerve endings in the epidermis and centrally within superficial lamina of the dorsal horn in the spinal cord. NaV1.7 is also expressed in sympathetic neurons and olfactory sensory neurons.

  • NaV1.7 produces a rapidly activating and inactivating but slowly repriming current that is sensitive to nanomolar concentrations of tetrodotoxin, and a robust ramp current in response to small, slow depolarizations, suggesting that NaV1.7 acts as a threshold channel.

  • The ability of NaV1.7 to boost subthreshold stimuli, together with its presence at nerve endings in the epidermis and in the dorsal horn, increases the probability of neurons reaching their threshold for firing action potentials, and may facilitate neurotransmitter release onto second-order neurons.

  • Genetic and functional studies have linked gain-of-function mutations of SCN9A with pain disorders such as inherited erythromelalgia and paroxysmal pain disorder, whereas loss-of-function mutations are linked to complete insensitivity to pain that may be accompanied by anosmia. Other gain-of-function variants in NaV1.7 are risk factors for painful small-fibre neuropathy.

  • Atomic structural modelling of NaV1.7 based on the crystal structure of other ion channels has identified the activation gate of the NaV1.7, and together with thermodynamic analysis of 'seed' mutations that increase drug responsiveness, may allow the identification of channel variants that enhance responsiveness to pharmacotherapies.

  • The central role of NaV1.7 in pain signalling and the lack of cognitive, motor and cardiac deficits in patients with NaV1.7-linked complete insensitivity to pain has made this channel a major focus for the development of small-molecule blockers and other biological approaches for the treatment of pain.

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Figure 1: Domain structure of NaV1.7 and locations of characterized mutations in NaV1.7-related pain disorders.
Figure 2: Pain signal transmission from peripheral terminals of DRG neurons that form synapses onto second-order neurons within the spinal cord.
Figure 3: Biophysical properties of wild-type and mutant NaV1.7 channels.
Figure 4: The F1449V mutation in NaV1.7 makes DRG neurons hyperexcitable.
Figure 5: A model of the putative activation gate of NaV1.7.


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The authors thank the members of their group for valuable discussions. Work in the authors' laboratory is supported in part by grants from the Rehabilitation Research and Development Service and Medical Research Service, US Department of Veterans Affairs, and from the Erythromelalgia Association. The Center for Neuroscience and Regeneration Research is a collaboration between the Paralyzed Veterans of America and Yale University, Connecticut, USA.

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Correspondence to Stephen G. Waxman.

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Competing interests

Pfizer has provided a research grant, administered through Yale University, Connecticut, USA, in support of research funding for S.G.W. and S.D.H.

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Online Mendelian Inheritance in Man (OMIM)


Center for Neuroscience and Regeneration Research, Yale School of Medicine


Neuropathic pain

Pain resulting from lesions or diseases of the somatosensory system.


Pain-sensing or damage-sensing neurons.


Refolding of a channel after opening and inactivating to restore a closed, but available channel. The channel is refractory to additional stimulations during repriming.

Ramp current

Inward current due to transient channel activation in response to the small, slow depolarization of cell membranes.


A collection of demyelinated and dysmyelinated axon sprouts and connective tissue that result from abortive regeneration of transected axons.

Inherited sodium channelopathies

Pathologies linked to mutations or functional variants in sodium channels that can be transmitted to progeny.

Fast inactivation

Inactivation (within milliseconds) of sodium channels occurs by blocking the cytoplasmic vestibule of the channel by a tetrapeptide (inactivation gate) within the linker joining domains III and IV, and terminating the inflow of sodium ions.


When one functional copy of a gene is not enough to prevent a deficit.

Atomic structural modelling

Construction of a model of a folded protein based on the atom coordinates of a related member of the family whose high-resolution crystal structure is determined and additional constraints derived from studies of distant members of the superfamily.

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Dib-Hajj, S., Yang, Y., Black, J. et al. The NaV1.7 sodium channel: from molecule to man. Nat Rev Neurosci 14, 49–62 (2013) doi:10.1038/nrn3404

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