Loss-of-function of Nav1.8/D1639N linked to human pain can be rescued by lidocaine

Abstract

Mutations in voltage-gated sodium channels are associated with altered pain perception in humans. Most of these mutations studied to date present with a direct and intuitive link between the altered electrophysiological function of the channel and the phenotype of the patient. In this study, we characterize a variant of Nav1.8, D1639N, which has been previously identified in a patient suffering from the chronic pain syndrome "small fiber neuropathy". Using a heterologous expression system and patch-clamp analysis, we show that Nav1.8/D1639N reduces current density without altering biophysical gating properties of Nav1.8. Therefore, the D1639N variant causes a loss-of-function of the Nav1.8 sodium channel in a patient suffering from chronic pain. Using immunocytochemistry and biochemical approaches, we show that Nav1.8/D1639N impairs trafficking of the channel to the cell membrane. Neither co-expression of β1 or β3 subunit, nor overnight incubation at 27 °C rescued current density of the D1639N variant. On the other hand, overnight incubation with lidocaine fully restored current density of Nav1.8/D1639N most likely by overcoming the trafficking defect, whereas phenytoin failed to do so. Since lidocaine rescues the loss-of-function of Nav1.8/D1639N, it may offer a future therapeutic option for the patient carrying this variant. These results demonstrate that the D1639N variant, identified in a patient suffering from chronic pain, causes loss-of-function of the channel due to impaired cell surface trafficking and that this trafficking defect can be rescued by lidocaine.

Impact of the NaV1.8 variant, A1073V, on post-sigmoidectomy pain and electrophysiological function in rat sympathetic neurons

“…However, carriers of the mutation were reported to be insensitive to pain while also being affected with "gastrointestinal disturbances." It should be noted that loss-of-function Na V polymorphisms have been reported to be linked to chronic pain patients (Kaluza et al 2018). That is, the in vitro experiments demonstrated that the Na V 1.8 D1639N variant exhibited decreased current density compared with wild-type-expressing cells as a result of impaired channel trafficking.…”

Familial episodic limb pain in kindreds with novel Nav1.9 mutations

“…It has recently been demonstrated that mutations in Nav channels that result in neurogenic diseases impair the expression level or trafficking of the channels to the cell membrane [35–39]. Nav channels are composed of a pore-forming α subunit and their associated β subunits that modulate channel expression levels, voltage dependence and kinetics [40, 41].…”

Trafficking mechanisms underlying Nav channel subcellular localization in neurons

“…Furthermore, M1841T Na v 1.1, a mutation associated with familial epilepsy, is a loss-offunction mutation that impairs forward trafficking to the surface, but surface expression can be restored by incubation at <30°C [144]. Mutation D1639N in Na v 1.8, identified in a human patient suffering from a chronic pain syndrome (Small Fiber Neuropathy) [145], impairs trafficking of Na v 1.8 to the plasma membrane [146]. Interestingly, the authors were able to restore its trafficking, in vitro, by overnight treatment with lidocaine.…”