Defining the Functional Role of NaV1.7 in Human Nociception

Lucy A Mcdermott,Greg A Weir,Andreas C Themistocleous,Andrew R Segerdahl,Iulia Blesneac,Georgios Baskozos,Alex J Clark,Val Millar,Liam J Peck,Daniel Ebner,Irene Tracey,Jordi Serra,David L Bennett

doi:10.1016/j.neuron.2019.01.047

Lucy A Mcdermott, Greg A Weir + Show 11 more

Open Access

https://doi.org/10.1016/j.neuron.2019.01.047

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Abstract

SummaryLoss-of-function mutations in NaV1.7 cause congenital insensitivity to pain (CIP); this voltage-gated sodium channel is therefore a key target for analgesic drug development. Utilizing a multi-modal approach, we investigated how NaV1.7 mutations lead to human pain insensitivity. Skin biopsy and microneurography revealed an absence of C-fiber nociceptors in CIP patients, reflected in a reduced cortical response to capsaicin on fMRI. Epitope tagging of endogenous NaV1.7 revealed the channel to be localized at the soma membrane, axon, axon terminals, and the nodes of Ranvier of induced pluripotent stem cell (iPSC) nociceptors. CIP patient-derived iPSC nociceptors exhibited an inability to properly respond to depolarizing stimuli, demonstrating that NaV1.7 is a key regulator of excitability. Using this iPSC nociceptor platform, we found that some NaV1.7 blockers undergoing clinical trials lack specificity. CIP, therefore, arises due to a profound loss of functional nociceptors, which is more pronounced than that reported in rodent models, or likely achievable following acute pharmacological blockade.Video

Highlights

Bi-allelic inactivating mutations in SCN9A, which encodes the voltage-gated sodium channel (VGSC) NaV1.7, result in the striking clinical phenotype of congenital insensitivity to pain (CIP) (Cox et al, 2006; Goldberg et al, 2007)
Quantitative sensory testing (QST) confirmed the insensitivity to pain phenotype as neither noxious temperature nor noxious mechanical stimuli were felt as painful (Figure 1A)
To study the function of NaV1.7 independent of inter-patient genetic variability, we introduced a homozygous SCN9A frameshift mutation (N842X) into a healthy control induced pluripotent stem cell (iPSC) line (HC1), generating a NaV1.7 knockout (NaV1.7 KO) (Figure S4B)

Summary

Introduction

Bi-allelic inactivating mutations in SCN9A, which encodes the voltage-gated sodium channel (VGSC) NaV1.7, result in the striking clinical phenotype of congenital insensitivity to pain (CIP) (Cox et al, 2006; Goldberg et al, 2007). These individuals do not perceive pain in response to noxious stimuli (Bennett and Woods, 2014), be it mechanical, thermal, or chemical in form. The only other clinical feature of bi-allelic loss-of-function (LOF) NaV1.7 mutations is anosmia (Weiss et al, 2011). These findings have led to extensive interest in selectively targeting NaV1.7 as a means to develop novel analgesics

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