The role of Nav1.7 in human nociceptors: Insights from human induced pluripotent stem cell-derived sensory neurons of erythromelalgia patients

Meents JE, Bressan E, Sontag S, Foerster A, Hautvast P, Rösseler C, Hampl M, Schüler H, Goetzke R, Le TKC, Kleggetveit IP, Le Cann K, Kerth C, Rush AM, Rogers M, Kohl Z, Schmelz M, Wagner W, Jørum E, Namer B, Winner B, Zenke M, Lampert A (2019)

Publication Language: English

Publication Type: Journal article

Publication year: 2019

Journal

Pain Lippincott, Williams & Wilkins

Book Volume: 160

Pages Range: 1327-1341

Journal Issue: 6

DOI: 10.1097/j.pain.0000000000001511

Abstract

The chronic pain syndrome inherited erythromelalgia (IEM) is attributed to mutations in the voltage-gated sodium channel (NaV) 1.7. Still, recent studies targeting NaV1.7 in clinical trials have provided conflicting results. Here, we differentiated induced pluripotent stem cells from IEM patients with the NaV1.7/I848T mutation into sensory nociceptors. Action potentials in these IEM nociceptors displayed a decreased firing threshold, an enhanced upstroke, and afterhyperpolarization, all of which may explain the increased pain experienced by patients. Subsequently, we investigated the voltage dependence of the tetrodotoxin-sensitive NaV activation in these human sensory neurons using a specific prepulse voltage protocol. The IEM mutation induced a hyperpolarizing shift of NaV activation, which leads to activation of NaV1.7 at more negative potentials. Our results indicate that NaV1.7 is not active during subthreshold depolarizations, but that its activity defines the action potential threshold and contributes significantly to the action potential upstroke. Thus, our model system with induced pluripotent stem cell-derived sensory neurons provides a new rationale for NaV1.7 function and promises to be valuable as a translational tool to profile and develop more efficacious clinical analgesics.

Authors with CRIS profile

Zacharias Kohl Medizinische Fakultät Barbara Namer Medizinische Fakultät Beate Winner Professur für Stammzell-Modelle seltener neuraler Erkrankungen

Involved external institutions

Universitätsklinikum Aachen (UKA) DE Germany (DE) Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen DE Germany (DE) Metrion Biosciences Limited GB United Kingdom (GB) Ruprecht-Karls-Universität Heidelberg DE Germany (DE) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet NO Norway (NO)

How to cite

APA:

Meents, J.E., Bressan, E., Sontag, S., Foerster, A., Hautvast, P., Rösseler, C.,... Lampert, A. (2019). The role of Nav1.7 in human nociceptors: Insights from human induced pluripotent stem cell-derived sensory neurons of erythromelalgia patients. Pain, 160(6), 1327-1341. https://dx.doi.org/10.1097/j.pain.0000000000001511

MLA:

Meents, Jannis E., et al. "The role of Nav1.7 in human nociceptors: Insights from human induced pluripotent stem cell-derived sensory neurons of erythromelalgia patients." Pain 160.6 (2019): 1327-1341.

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