Shaping human nociceptor excitability via activation of sodium channel Nav1.9. Building a basis for innovative pain therapies.

• Applicant: Professorin Dr. Angelika Lampert
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 386872283

• Final Report Year: 2023

Final Report Abstract

In this successful DFG project, we investigated the impact of voltage-gated sodium channels in regulating the excitability of neurons with specific focus on the subtype Nav1.9 and sensory neurons. To this end, we first investigated the biophysics of Nav gating in the context of disease. As the voltage-gated sodium channel Nav1.9 is thought to play a pivotal role in setting the resting membrane potential and fine-tuning action potentials, we aimed to investigate its biophysics and pharmacology/toxicology in detail. As this channel is historically hard to express, we used a chimera with Nav1.4, which renders measurable currents in heterologous expression systems. As translation from heterologous expression systems or rodents to human in pain research is limited, we optimized the differentiation of induced pluripotent stem cells (iPSCs) of healthy controls and patients suffering from pain or other diseases. We differentiated these iPSCs into neurons and assessed their excitability by patchclamp or multi-electrode-array to better understand the impact of genetic variation on neuronal excitability. In a proof-of-concept study, we were able to show the efficacy of lacosamide in ending the 10-year long suffering of a pain patient, by identifying treatment on patient-derived sensory neurons in the dish.

Publications

• Loss-of-function of Nav1.8/D1639N linked to human pain can be rescued by lidocaine. Pflügers Archiv - European Journal of Physiology, 470(12), 1787-1801.
  Kaluza, Luisa; Meents, Jannis E.; Hampl, Martin; Rösseler, Corinna; Hautvast, Petra A. I.; Detro-Dassen, Silvia; Hausmann, Ralf; Schmalzing, Günther & Lampert, Angelika
  
• β1 subunit stabilises sodium channel Nav1.7 against mechanical stress. The Journal of Physiology, 596(12), 2433-2445.
  Körner, Jannis; Meents, Jannis; Machtens, Jan‐Philipp & Lampert, Angelika
  
• Pain relief in a neuropathy patient by lacosamide: Proof of principle of clinical translation from patient-specific iPS cell-derived nociceptors. EBioMedicine, 39, 401-408.
  Namer, Barbara; Schmidt, Diana; Eberhardt, Esther; Maroni, Michele; Dorfmeister, Eva; Kleggetveit, Inge Petter; Kaluza, Luisa; Meents, Jannis; Gerlach, Aaron; Lin, Zhixin; Winterpacht, Andreas; Dragicevic, Elena; Kohl, Zacharias; Schüttler, Jürgen; Kurth, Ingo; Warncke, Torhild; Jorum, Ellen; Winner, Beate & Lampert, Angelika
  
• 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.
  Meents, Jannis E.; Bressan, Elisangela; Sontag, Stephanie; Foerster, Alec; Hautvast, Petra; Rösseler, Corinna; Hampl, Martin; Schüler, Herdit; Goetzke, Roman; Le, Thi Kim Chi; Kleggetveit, Inge Petter; Le Cann, Kim; Kerth, Clara; Rush, Anthony M.; Rogers, Marc; Kohl, Zacharias; Schmelz, Martin; Wagner, Wolfgang; Jørum, Ellen; ... & Lampert, Angelika
  
• β1 and β3 subunits amplify mechanosensitivity of the cardiac voltage-gated sodium channel Nav1.5. Pflügers Archiv - European Journal of Physiology, 471(11-12), 1481-1492.
  Maroni, Michele; Körner, Jannis; Schüttler, Jürgen; Winner, Beate; Lampert, Angelika & Eberhardt, Esther
  
• Characterization of Synthetic Tf2 as a NaV1.3 Selective Pharmacological Probe. Biomedicines, 8(6), 155.
  Israel, Mathilde R.; Dash, Thomas S.; Bothe, Stefanie N.; Robinson, Samuel D.; Deuis, Jennifer R.; Craik, David J.; Lampert, Angelika; Vetter, Irina & Durek, Thomas
  
• Dataset of electrophysiological patch-clamp recordings of the effect of the compounds deltamethrin, ATx-II and β4-peptide on human cardiac Nav1.5 sodium channel gating properties. Data in Brief, 31, 105844.
  Thull, Sarah; Neacsu, Cristian; O.'Reilly, Andrias O.; Bothe, Stefanie; Hausmann, Ralf; Huth, Tobias; Meents, Jannis & Lampert, Angelika
  
• Human sensory neurons derived from pluripotent stem cells for disease modelling and personalized medicine. Neurobiology of Pain, 8, 100055.
  Lampert, Angelika; Bennett, David L.; McDermott, Lucy A.; Neureiter, Anika; Eberhardt, Esther; Winner, Beate & Zenke, Martin
  
• Mechanism underlying hooked resurgent-like tail currents induced by an insecticide in human cardiac Nav1.5. Toxicology and Applied Pharmacology, 397, 115010.
  Thull, Sarah; Neacsu, Cristian; O.'Reilly, Andrias O.; Bothe, Stefanie; Hausmann, Ralf; Huth, Tobias; Meents, Jannis & Lampert, Angelika
  
• PRDM8 reveals aberrant DNA methylation in aging syndromes and is relevant for hematopoietic and neuronal differentiation. Clinical Epigenetics, 12(1).
  Cypris, Olivia; Eipel, Monika; Franzen, Julia; Rösseler, Corinna; Tharmapalan, Vithurithra; Kuo, Chao-Chung; Vieri, Margherita; Nikolić, Miloš; Kirschner, Martin; Brümmendorf, Tim H.; Zenke, Martin; Lampert, Angelika; Beier, Fabian & Wagner, Wolfgang
  
• Uncoupling sodium channel dimers restores the phenotype of a pain‐linked Nav1.7 channel mutation. British Journal of Pharmacology, 177(19), 4481-4496.
  Rühlmann, Annika H.; Körner, Jannis; Hausmann, Ralf; Bebrivenski, Nikolay; Neuhof, Christian; Detro‐Dassen, Silvia; Hautvast, Petra; Benasolo, Carène A.; Meents, Jannis; Machtens, Jan‐Philipp; Schmalzing, Günther & Lampert, Angelika
  
• Assessing the impact of pain-linked Nav1.7 variants: An example of two variants with no biophysical effect. Channels, 15(1), 208-228.
  Le Cann, Kim; Meents, Jannis E.; Sudha, Bhagavath Eswaran Vishal; Dohrn, Maike F.; Bott, Raya; Maier, Andrea; Bialer, Martin; Hautvast, Petra; Erickson, Andelain; Rolke, Roman; Rothermel, Markus; Körner, Jannis; Kurth, Ingo & Lampert, Angelika
  
• Phosphorylation of a chronic pain mutation in the voltage-gated sodium channel Nav1.7 increases voltage sensitivity. Journal of Biological Chemistry, 296, 100227.
  Kerth, Clara M.; Hautvast, Petra; Körner, Jannis; Lampert, Angelika & Meents, Jannis E.
  
• The difficulty to model Huntington’s disease in vitro using striatal medium spiny neurons differentiated from human induced pluripotent stem cells. Scientific Reports, 11(1).
  Le Cann, Kim; Foerster, Alec; Rösseler, Corinna; Erickson, Andelain; Hautvast, Petra; Giesselmann, Sebastian; Pensold, Daniel; Kurth, Ingo; Rothermel, Markus; Mattis, Virginia B.; Zimmer-Bensch, Geraldine; von Hörsten, Stephan; Denecke, Bernd; Clarner, Tim; Meents, Jannis & Lampert, Angelika
  
• The insecticide deltamethrin enhances sodium channel slow inactivation of human Nav1.9, Nav1.8 and Nav1.7. Toxicology and Applied Pharmacology, 428, 115676.
  Bothe, Stefanie Nicole & Lampert, Angelika
  
• The Potential Effect of Nav1.8 in Autism Spectrum Disorder: Evidence From a Congenital Case With Compound Heterozygous SCN10A Mutations. Frontiers in Molecular Neuroscience, 14.
  Heinrichs, Björn; Liu, Baowen; Zhang, Jin; Meents, Jannis E.; Le, Kim; Erickson, Andelain; Hautvast, Petra; Zhu, Xiwen; Li, Ningbo; Liu, Yi; Spehr, Marc; Habel, Ute; Rothermel, Markus; Namer, Barbara; Zhang, Xianwei; Lampert, Angelika & Duan, Guangyou
  
• Sodium Channels and Local Anesthetics—Old Friends With New Perspectives. Frontiers in Pharmacology, 13.
  Körner, Jannis; Albani, Simone; Sudha, Bhagavath Eswaran Vishal; Roehl, Anna B.; Rossetti, Giulia & Lampert, Angelika
  
• Cold and warmth intensify pain-linked sodium channel gating effects and persistent currents. Journal of General Physiology, 155(9).
  Kriegeskorte, Sophia; Bott, Raya; Hampl, Martin; Korngreen, Alon; Hausmann, Ralf & Lampert, Angelika