Defining the functional role of NaV1.7 in human nociception

McDermott, L. A. et al. (2019) Defining the functional role of NaV1.7 in human nociception. Neuron, 101(5), 905-919.e8. (doi: 10.1016/j.neuron.2019.01.047) (PMID:30795902) (PMCID:PMC6424805)

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Abstract

Loss-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.

Item Type:Articles
Additional Information:D.L.B. is a senior Wellcome clinical scientist (202747/Z/16/Z). D.L.B. and I.T. are members of the Wellcome Pain Consortium (102645). This work was partly funded by the European Union’s Horizon 2020 research and innovation programme under 633491 (DOLORisk). The research leading to these results has also received support from the Innovative Medicines Initiative Joint Undertaking (115439), resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ kind contribution. D.L.B., I.B., and A.C.T. are members of the DOLORisk Consortium funded by the European Commission Horizon 2020 (ID633491). D.L.B. and A.C.T. are members of the International Diabetic Neuropathy Consortium, the Novo Nordisk Foundation (NNF14SA0006).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Weir, Dr Gregory
Authors: McDermott, L. A., Weir, G. A., Themistocleous, A. C., Segerdahl, A. R., Blesneac, I., Basakozos, G., Clark, A. J., Millar, V., Peck, L. J., Ebner, D., Tracey, I., Serra, J., and Bennett, D. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Neuron
Publisher:Elsevier (Cell Press)
ISSN:0896-6273
ISSN (Online):1097-4199
Published Online:19 February 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Neuron 101(5): 905-919.e8
Publisher Policy:Reproduced under a Creative Commons License

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