Slow inactivation of nociceptive sodium channels: crucial gating mechanism and its role in the origin of pain

• Antragstellerin: Professorin Dr. Angelika Lampert
• Fachliche Zuordnung: Anatomie und Physiologie
• Förderung: Förderung von 2009 bis 2014
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 160565930

Chronic pain represents a severe, debilitating condition. Although up to 10% of the worldwide population is affected, current treatment strategies are often inadequate. Recently, loss of function mutations in human voltage-gated sodium channel Nav1.7, which is expressed in peripheral nociceptors, has been linked to complete insensitivity to pain. Vice versa, gain of function mutations in Nav1.7 lead to an inherited chronic neuropathic pain syndrome, erythromelalgia. All erythromelalgia mutations shift the channel s activation to more negative potentials, rendering the expressing cells more excitable. Most of them also show prominent enhancement of slow inactivation, a gating mode that reduces the number of available channels and that recently has become of interest for pain-related drug development. This project aims to explore the structure and function of slow inactivation and its role in the generation of action potential and pain-related repetitive firing with electrophysiology and molecular biology methods. I plan to address three questions: 1. Which channel structures are responsible for the different slow inactivation properties of subtypes of nociceptive sodium channels? 2. What is the contribution of slow inactivation to action potential formation and repetitive firing in pain neurons? 3. Is modulation of slow inactivation in sodium channels suitable as therapeutic principle in a mouse model of neuropathic pain? Answering these questions will further our understandings of molecular sodium channel gating and help developing targeted medication with fewer side effects against pain.

• DFG-Verfahren: Sachbeihilfen
• Großgeräte: Patch-Clamp-Setup
• Gerätegruppe: 5040 Spezielle Mikroskope (außer 500-503)