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.
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Human sodium channel NaV1.7 in induced pluripotent stem cell–derived sensory neurons sets the action potential threshold but does not support subthreshold depolarizations.
aInstitute of Physiology, Medical Faculty, RWTH Aachen University, Aachen, Germany. Dr. Bressan is now with the German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
bDepartment of Cell Biology, Institute for Biomedical Engineering, Medical Faculty, RWTH Aachen University, Aachen, Germany. Dr. Sontag is now with the Taconic Biosciences GmbH, Köln, Germany
cHelmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany
dInstitute for Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
eInstitute of Human Genetics, Uniklinik RWTH Aachen, Aachen, Germany
fDivision of Stem Cell Biology and Cellular Engineering, Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany
gSection of Clinical Neurophysiology, Department of Neurology, Oslo University Hospital-Rikshospitalet, Oslo, Norway
hMetrion Biosciences, Cambridge, United Kingdom
iDepartment of Molecular Neurology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
jDepartment of Experimental Pain Research Mannheim, Heidelberg University, Mannheim, Germany
kInstitute of Clinical Medicine, University of Oslo, Oslo, Norway
lDepartment of Stem Cell Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
Corresponding author. Address: Institute of Physiology, Medical Faculty, RWTH Aachen University, Pauwelsstr 30, 52074 Aachen, Germany. Tel.: 0049 241 8088810; fax: 0049 241 8082434. E-mail address: firstname.lastname@example.org (A. Lampert).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
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J.E. Meents, E. Bressan, S. Sontag, and A. Foerster contributed equally to this work.
Received September 13, 2018
Received in revised form January 09, 2019
Accepted January 25, 2019