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Diversity of composition and function of sodium channels in peripheral sensory neurons

Dib-Hajj, Sulayman D.; Waxman, Stephen G.

doi: 10.1097/j.pain.0000000000000353
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aDepartment of Neurology, Yale University School of Medicine, New Haven, CT, USA.

bCenter for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT, USA.

cRehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA

Correspondence author. Address: Neuroscience and Regeneration Research Center, VA Connecticut Healthcare System, 950 Campbell Ave, Bldg. 34, West Haven, CT 06516, USA. Tel.: (203)937-3802; fax: (203)937-3801. E-mail address: (S. D. Dib-Hajj).

The authors have no conflicts of interest to declare.

This work was supported in part by grants from the Rehabilitation Research Service and Medical Research Service, Department of Veterans Affairs (SDH and SGW), and the Erythromelalgia Association. The Center for Neuroscience & Regeneration Research is a Collaboration of the Paralyzed Veterans of America with Yale University.

In Dorsal root ganglion (DRG) neurons, the integration and transmission of signals from peripheral sensory transducers depend on voltage-gated sodium channels (Navs) which underlie the initiation of action potentials in peripheral terminals and their propagation to the central nervous system.

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1. Dorsal root ganglion neurons express diverse sodium channels

1.1. Dynamic expression of Navs

Dynamic expression of several Navs with distinct gating and pharmacological properties has been reported in DRG neurons during development and after injury.4 Robust levels of Nav1.6, Nav1.7, Nav1.8, and Nav1.9 are found in embryonic and adult DRG neurons. Nav1.3 is expressed during embryonic and neonatal stages and is upregulated in adult neurons by injury or disease.4 Reducing Nav1.3 levels attenuates injury-induced pain.13

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1.2. Contribution of Nav isoforms to action potential

Navs in DRG neurons manifest distinct voltage dependence, kinetics, and pharmacological properties,12 which regulate neuronal firing patterns. Based on their ability to boost subthreshold stimuli (Nav1.3 and Nav1.7) or hyperpolarized and persistent current (Nav1.9), these channels have been considered threshold channels for action potential firing. Nav1.3, Nav1.6 (especially at nodes of Ranvier), and Nav1.8 contribute most of the current for the action potential in the neurons where they are expressed; regulation of slow inactivation and use dependence of Nav1.8 contributes to differential adaptation of action potentials in IB4+ vs IB4− small DRG neurons.3

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1.3. Species-specific differences in Navs properties

Nav1.89 and Nav1.95 manifest species-specific differences in channel gating, which may reflect divergence of primary amino acid sequence of the channel’s orthologues from different species. Importantly, recent evidence demonstrated differences in DRG neuronal firing attributable to altered gating of human vs rodent Nav1.8 channels.9

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2. Mutations in Navs cause human pain disorders

2.1. Gain-of-function mutations in pain disorders

Dominant mutations in SCN9A (encodes Nav1.7) and SCN11A (encodes Nav1.9) segregate with symptoms in familial pain disorders,2,6,15 which confer gain-of-function attributes to the channels and increase excitability of DRG neurons leading to pain. Based on these well-studied rare genetic disorders, variants in peripheral Navs, coupled with functional testing in native DRG neurons, have been linked to common pain disorders.7,8,10

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2.2. Loss-of-function mutations in SCN9A cause insensitivity to pain

Recessive loss-of-function mutations in SCN9A have been identified in patients with congenital insensitivity to pain (CIP).2,6 Patients with Nav1.7-related CIP do not manifest deficits in cognitive, cardiac, or motor function but can be anosmic. Although a gain-of-function mutation in SCN11A has been reported to cause CIP,11 the mechanism is not clear, given that other gain-of-function mutations in SCN11A have been linked to episodic familial pain and peripheral neuropathies.10,15

These studies have highlighted peripheral Navs as opportune targets for the development of novel non-addictive pain therapeutics with minimal side effects.

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