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Review
. 2020 Jul;472(7):865-880.
doi: 10.1007/s00424-020-02419-9. Epub 2020 Jun 29.

Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels

Mark D Baker  1 , Mohammed A Nassar  2
Affiliations
Review

Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels

Mark D Baker et al. Pflugers Arch. 2020 Jul.

Abstract

Chronic pain is a global problem affecting up to 20% of the world's population and has a significant economic, social and personal cost to society. Sensory neurons of the dorsal root ganglia (DRG) detect noxious stimuli and transmit this sensory information to regions of the central nervous system (CNS) where activity is perceived as pain. DRG neurons express multiple voltage-gated sodium channels that underlie their excitability. Research over the last 20 years has provided valuable insights into the critical roles that two channels, NaV1.7 and NaV1.9, play in pain signalling in man. Gain of function mutations in NaV1.7 cause painful conditions while loss of function mutations cause complete insensitivity to pain. Only gain of function mutations have been reported for NaV1.9. However, while most NaV1.9 mutations lead to painful conditions, a few are reported to cause insensitivity to pain. The critical roles these channels play in pain along with their low expression in the CNS and heart muscle suggest they are valid targets for novel analgesic drugs.

Keywords: Dorsal root ganglia; Human mutations; Nav1.7; Nav1.9; Pain; Painful conditions; Voltage-gated sodium channels.

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Figures

Fig. 1
Fig. 1
Topological representation of SCN9A mutations that cause PEM. A VGSC α-subunit consists of four homologous domains (DI-DIV). Each domain consists of six transmembrane segments. Three intracellular loops (L1-L2) connect the four domains. Note that most mutations are localised to domains I and II. Structures are not drawn to scale
Fig. 2
Fig. 2
Topological representation of mutations that cause PEPD in the α-subunit of NaV1.7. Note that most mutations are localised in L3 and domains III and IV. Structures are not drawn to scale
Fig. 3
Fig. 3
Topological representation of SCN9A mutations that cause heritable SFN. Most mutations associated with SFN are found clustered around L1. Structures are not drawn to scale
Fig. 4
Fig. 4
Topological representation of SCN9A mutations that are linked to epilepsies
Fig. 5
Fig. 5
Topological representation of SCN9A mutations that cause CIP. Mutations associated with CIP are widely distributed throughout the α-subunit
Fig. 6
Fig. 6
a Upregulation of Nav1.9 in an Nav1.8 knockout neuron, following the introduction of 500 μM GTP-γ-S into the cell interior for 12 min. b Upregulation of Nav1.9 using intracellular GTP-γ-S gives rise to changes in the firing properties of Nav1.8 knockout neuron, with reductions in current and voltage threshold, recorded from a holding potential of − 90 mV. The upregulated current gives rise to plateau potentials (arrow). Reproduced from [6], with permission
Fig. 7
Fig. 7
Topological representation of SCN11A mutations. Notice that all CIP causing mutations (red) are located in the transmembrane segment 6
See this image and copyright information in PMC

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