Biophysical characterization of heterologously expressed pain-related NaV mutants

This project is a project of the joint research consortium “Sodium channel‐related pain disorders:   From molecular mechanisms towards personalized treatment” formerly funded by the Aachener Interdisziplinäres Zentrum für Klinische Forschung (IZKF) of the Faculty of Medicine of RWTH Aachen University.

Chronic pain is a therapeutic challenge. Genetically encoded pain syndromes offer the chance to understand mechanisms of chronic pain on a genetic, cellular and molecular level and former studies could attribute multiple pain disorders to mutations in voltage-gated sodium channels (Dohrn et al., 2019). Human voltage-gated Na⁺ channels (hNa_Vs) are membrane proteins responsible for the rising phase of action potentials of excitable cells.

In one part of the project (principal investigator Prof. Dr. med. Ralf Hausmann) we use an electrophysiological approach that allows us to address whether a particular pain-associated Na_V variant affects Na_V channel gating and provides novel insights into the biophysics of Na_V channels in general and the mechanisms of how Na_V mutants induce pain (Kaluza et al., 2018).

In another part of the project (principal investigator Prof. Dr. med. Günther Schmalzing) we use biochemical techniques to address the expression level, stability, oligomerization and intra-cellular trafficking of recombinant hNa_V1.7 and hNa_V1.8 alone or together with auxiliary proteins including hβ subunits. These techniques allow addressing effects of point mutations that map to protein regions with known or unknown functions.

Our dual electrophysiological-biochemical approach will allow us to address important questions such as whether a particular pain-associated Na_V variant affects protein stability, dimerization or biophysical characteristics of activation or inactivation gating.

Further information on the research consortium SCN^Aachen are available under the following LINK.

_{Dohrn et al., 2019. Neuropathische Schmerzsyndrome bei Ionenkanalerkrankungen. Der Internist 2019, 60:90-97.}

_{Kaluza et al., 2018. Loss-of-function of Nav1.8/D1639N linked to human pain can be rescued by lidocaine. Pflugers Arch. 2018, 470:1787-1801.}