The role of Nav1.7 in human nociceptors: insights from human induced pluripotent stem cell-derived sensory neurons of erythromelalgia patients
| Autor: | Roman Goetzke, Herdit M. Schüler, Marc Rogers, Ellen Jørum, Angelika Lampert, Martin Hampl, Elisangela Bressan, Anthony M. Rush, Martin Zenke, Zacharias Kohl, Clara M. Kerth, Thi Kim Chi Le, Barbara Namer, Alec Foerster, Petra Hautvast, Martin Schmelz, Corinna Rösseler, Wolfgang Wagner, Kim Le Cann, Inge Petter Kleggetveit, Beate Winner, Jannis E. Meents, Stephanie Sontag |
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| Rok vydání: | 2019 |
| Předmět: |
Patch-Clamp Techniques
Action potential Action Potentials Membrane Potentials 0302 clinical medicine 030202 anesthesiology Ganglia Spinal pharmacology [Tetrodotoxin] pain Induced pluripotent stem cell Prepulse inhibition genetics [NAV1.7 Voltage-Gated Sodium Channel] NAV1.7 Voltage-Gated Sodium Channel Nociceptors Afterhyperpolarization cytology [Induced Pluripotent Stem Cells] Erythromelalgia metabolism [NAV1.7 Voltage-Gated Sodium Channel] iPS cells Neurology genetics [Pain] genetics [Erythromelalgia] Nociceptor sodium channel Research Paper physiology [Nociceptors] Sensory Receptor Cells Induced Pluripotent Stem Cells Pain Sensory system Tetrodotoxin physiopathology [Erythromelalgia] patch clamp 03 medical and health sciences methods [Patch-Clamp Techniques] stem cells medicine Voltage-gated sodium channel metabolism [Sensory Receptor Cells] Humans ddc:610 business.industry drug effects [Action Potentials] cytology [Ganglia Spinal] Sodium channel drug effects [Membrane Potentials] medicine.disease diagnosis [Pain] Electric Stimulation methods [Electric Stimulation] Anesthesiology and Pain Medicine nervous system Neurology (clinical) Inherited pain syndrome business Action potential firing Neuroscience Patch-clamp 030217 neurology & neurosurgery |
| Zdroj: | Pain Pain : the journal of the International Association for the Study of Pain 160(6), 1327-1341 (2019). doi:10.1097/j.pain.0000000000001511 Pain 160(6), 1327-1341 (2019). doi:10.1097/j.pain.0000000000001511 |
| ISSN: | 1872-6623 0304-3959 |
| DOI: | 10.1097/j.pain.0000000000001511 |
| Popis: | Supplemental Digital Content is Available in the Text. Human sodium channel NaV1.7 in induced pluripotent stem cell–derived sensory neurons sets the action potential threshold but does not support subthreshold depolarizations. 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. |
| Databáze: | OpenAIRE |
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