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

One of the most puzzling questions in present pain-related sodium channel research is how gain-of-function mutations in the subtype Nav1.9 can lead either to inherited pain syndromes or to loss-of-pain-perception. With the here proposed experiments we aim to decipher these two seemingly contradictory outcomes by using patch-clamp, pharmacology and multi-electrode array recordings on induced pluripotent stem cell derived human nociceptors of patients with Nav1.9 mutations causing an inherited pain syndrome or chronic insensitivity to pain. This approach enables us to assess the effects of Nav1.9 activity on neuronal excitability in its natural patient specific genetic background. To date, pain-linked mutations in the subtype Nav1.7 suggested that lowering its threshold is responsible for the clinical symptoms. As Nav1.7 and Nav1.9 differ significantly in their biophysical properties, we suggest that both channels follow distinct mechanisms to support pain phenotypes.Based on results from cell lines and rodent neurons we hypothesize that in human neurons Nav1.9 is relevant for action potential integrity and its hyperactivity may induce hyperexcitability or, finally, depolarization block. Selective strong enhancement of Nav1.9 activity may thus provide the basis for the development of new treatment strategies. We aim to pharmacologically activate and inhibit Nav channels and to stimulate stem cell derived nociceptors via extracellular electrodes using a multi-electrode array system. We will thus mimic either drug treatment or the application of skin electrodes which are currently used in therapeutic regimes. Thus, the here proposed experiments will help to understand complex nociceptor excitability, the interplay between Nav1.9 and Nav1.7, and to support the development of new, innovative pain therapy.

• DFG Programme: Research Grants