A sodium channel gene SCN9A polymorphism that increases nociceptor excitability

Abstract

Sodium channel Na(V)1.7, encoded by the SCN9A gene, is preferentially expressed in nociceptive primary sensory neurons, where it amplifies small depolarizations. In studies on a family with inherited erythromelalgia associated with Na(V)1.7 gain-of-function mutation A863P, we identified a nonsynonymous single-nucleotide polymorphism within SCN9A in the affected proband and several unaffected family members; this polymorphism (c. 3448C&T, Single Nucleotide Polymorphisms database rs6746030, which produces the amino acid substitution R1150W in human Na(V)1.7 [hNa(V)1.7]) is present in 1.1 to 12.7% of control chromosomes, depending on ethnicity. In this study, we examined the effect of the R1150W substitution on function of the hNa(V)1.7 channel, and on the firing of dorsal root ganglion (DRG) neurons in which this channel is normally expressed. We show that this polymorphism depolarizes activation (7.9-11mV in different assays). Current-clamp analysis shows that the 1150W allele depolarizes (6mV) resting membrane potential and increases ( approximately 2-fold) the firing frequency in response to depolarization in DRG neurons in which it is present. Our results suggest that polymorphisms in the Na(V)1.7 channel may influence susceptibility to pain.

Pain perception is altered by a nucleotide polymorphism in SCN9A

“…By contrast, most Na v 1.7 mutations associated with hyperexcitability and erythromelalgia have been reported to shift the voltage dependence of activation in the opposite, hyperpolarizing direction (26,28). Nevertheless, Na v 1.7-1150W produced hyperexcitability when expressed in small dorsal root ganglion neurons (27), a finding that is consistent with the clinical results presented here. The exact mechanism by which the minor A allele enhances pain sensitivity therefore remains unclear and might involve factors not present in the heterologous expression system, factors that affect expression, processing, or interaction of the Na v 1.7 protein in nociceptive neurons.…”

“…However, the observed biophysical effect is rather small and might be insufficient to explain the associated phenotype, because alteration of the slow inactivation of the Na v 1.7 conductance alone in the absence of altered voltage-dependent activation failed to change the firing properties in a computer model of nociceptive neurons (26). It is important to note that another recent study failed to observe a change in voltage dependence of slow inactivation, but instead reported a small depolarizing shift in the voltage dependence of activation for Na v 1.7-1150W compared to Na v 1.7-1150R currents (27). By contrast, most Na v 1.7 mutations associated with hyperexcitability and erythromelalgia have been reported to shift the voltage dependence of activation in the opposite, hyperpolarizing direction (26,28).…”

Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2

“…Finally, the mechanism(s) whereby CACNG2 polymorphisms affect spontaneous pain can be expected to inform our understanding of pain physiology. Several pain susceptibility genes have been identified previously based on family linkage studies or candidate gene approaches, including one remarkable example in which a genetic polymorphism directly related to mechanisms that regulate the electrical excitability of DRG neurons (Estacion et al 2009). …”

Evaluation of behavior and expression of NaV1.7 in dorsal root ganglia after sciatic nerve compression and application of nucleus pulposus in rats

“…To date, nine functionally distinct mammalian NaV channel alpha subunits (NaV1.1-NaV1.9) have been cloned, functionally expressed, and characterized [13]. In recent years, the tetrodotoxin-sensitive sodium channel NaV1.7 has emerged as an analgesic target and polymorphisms in the Na(V)1.7 channel may influence susceptibility to pain [14,15].…”