Small-Fiber Neuropathy Nav1.8 Mutation Shifts Activation to Hyperpolarized Potentials and Increases Excitability of Dorsal Root Ganglion Neurons

Abstract

Idiopathic small-fiber neuropathy (I-SFN), clinically characterized by burning pain in distal extremities and autonomic dysfunction, is a disorder of small-caliber nerve fibers of unknown etiology with limited treatment options. Functional variants of voltage-gated sodium channel Na v 1.7, encoded by SCN9A, have been identified in approximately one-third of I-SFN patients. These variants render dorsal root ganglion (DRG) neurons hyperexcitable. Sodium channel Na v 1.8, encoded by SCN10A, is preferentially expressed in small-diameter DRG neurons, and produces most of the current underlying the upstroke of action potentials in these neurons. We previously demonstrated two functional variants of Na v 1.8 that either enhance ramp current or shift activation in a hyperpolarizing direction, and render DRG neurons hyperexcitable, in I-SFN patients with no mutations of SCN9A. We have now evaluated additional I-SFN patients with no mutations in SCN9A, and report a novel I-SFN-related Na v 1.8 mutation I1706V in a patient with painful I-SFN. Whole-cell voltage-clamp recordings in small DRG neurons demonstrate that the mutation hyperpolarizes activation and the response to slow ramp depolarizations. However, it decreases fractional channels resistant to fast inactivation and reduces persistent currents. Current-clamp studies reveal that mutant channels decrease current threshold and increase the firing frequency of evoked action potentials within small DRG neurons. These observations suggest that the effects of this mutation on activation and ramp current are dominant over the reduced persistent current, and show that these pro-excitatory gating changes confer hyperexcitability on peripheral sensory neurons, which may contribute to pain in this individual with I-SFN.

Sodium channel NaV1.9 mutations associated with insensitivity to pain dampen neuronal excitability

“…Notably, when we injected current into nontransfected cells to produce membrane depolarizations similar to those caused by expression of L1302F (+11.5 mV) or L811P (+8.2 mV), we observed a reduced ability to fire action potentials. These findings are in contrast to our previous observations that a 4-to 6-mV depolarization in the resting potential of DRG neurons associated with multiple Na V 1.9 as well as Na V 1.7 mutations results in neuronal hyperexcitability and paroxysmal pain disorders (27,34,(53)(54)(55). These divergent observations regarding the effects of mutations on neuronal excitability are explained by the U-shaped relationship between resting potential and current threshold ( Figure 6A), which demonstrates hyperexcitability of neurons with a moderately depolarized RMP and hypoexcitability of neurons with a severely depolarized RMP.…”

“…Mutations in Na V 1.7 and Na V 1.8 have been extensively analyzed, and a clear genotypephenotype correlation has emerged (2,27,28). For Na V 1.7, mutations producing gain-of-function biophysical changes at the channel level are associated with disorders of paroxysmal pain (inherited erythromelalgia, paroxysmal extreme pain disorder), whereas those with loss-of-function properties are associated with congenital insensitivity to pain (CIP).…”

Topisches Ambroxol zur Behandlung neuropathischer Schmerzen

“…Auch die Attackenreduktion bei jedem unserer 5 betroffenen Patienten ist so eventuell erklärbar. Eine gesteigerte Na v 1.8-Expression findet sich ferner bei diabetischer Polyneuropathie [30], Smallfiber-Neuropathie [19], Radikulopathien [17,44], Trigeminusneuralgie [41], aber auch bei Arthrosen [39,43] und Knochenmetastasen [33]. Die Na v 1.8-Blockade, z.…”

NaV1.9: a sodium channel linked to human pain

“…Na V 1.7 and Na V 1.8 channels have garnered intense interest because of evidence for their role in human pain disorders [2][3][4][5] , whereas there has previously been no such evidence for Na V 1.9. Our understanding of Na V 1.9 in general has also lagged behind as, unlike Na V 1.7 and Na V 1.8, it has proved difficult to study Na V 1.9 in heterologous expression systems, because it is only expressed at low levels and is difficult to study in isolation in native neurons.…”