81: To Reopen Or Not To Reopen - A Comparative Analysis Of Resurgent Sodium Currents

Topic: Basic Science
Subtopic: Non-specific to any diagnosis (including studies in healthy animals), Electrophysiology

Background and Aims: Voltage-gated sodium channels (VGSCs) are key regulators of cellular excitability and are typically characterized by their activation and inactivation dynamics. When Navs interact with endogenous blocking peptides like the C-terminal end of Navβ4, they can escape this familiar pattern and produce a second “resurgent” inward current. Resurgent currents help regulate excitability and are associated with various diseases such as neuropathic pain in the event of pathological changes. Here we aim to compare resurgent currents from various VGSCs at different temperatures.

Methods: HEK cells, stably expressing Nav1.2, Nav1.3, Nav1.6 and Nav1.7 were cultured under standard in vitro conditions (5% CO2, 37°C). Sodium currents were measured at 15°C, 25°C or 35°C in the presence of 200 µM recombinant β4-peptide using an automated patch clamp system. A combined protocol for the recording of standard activation and inactivation parameters was followed by three protocols (stable prepulse voltage, variable prepulse voltage, variable prepulse duration) to investigate the dynamics of the resurgent currents produced by the different VGSCs.

Results: Increasing temperatures induced a hyperpolarizing shift of activation, while inactivation shifted to more depolarized values. All four VGSCs were able to generate resurgent currents at 15°C, 25°C, and 35°C. Overall colder temperatures, a more depolarized prepulse voltage and shortened prepulse duration supported larger resurgent currents. However, Nav1.7 produced smaller and less pronounced resurgent currents compared to Nav1.2, Nav1.3, and Nav1.6. The most pronounced resurgent currents were observed in recordings of Nav1.3.

Conclusions: Taken together, our data indicate that VGSC family members differ in their capacity to generate resurgent currents and in their sensitivity to ambient temperature. As sodium channels have been previously implicated in peripheral and central temperature sensing and regulation, these findings suggest that temperature-dependent resurgent currents may contribute to thermonociceptive signaling. Moreover, aberrant resurgent currents have been linked to neuropathic pain states, including chemotherapy-induced peripheral neuropathies. Our dataset provides a reference for studying resurgent currents in pain-related sodium channel mutations and pharmacology, and we will extend it to additional VGSC subtypes in future work.

References: NA

Presenting Author: Pascal Röderer
Submitting Author: Pascal Röderer

Senior Author: Angelika Lampert

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Marie Liselott Mehlfeldt - 1) Institute of Neurophysiology, Uniklinik RWTH Aachen University, Aachen, Germany 2) Scientific Center for Neuropathic Pain Aachen SCN-AACHEN, Uniklinik RWTH Aachen University, Aachen, Germany 3) Institute for Computational Biomedicine and Disease modelling with focus on phase transitions between phenotypes, RWTH Aachen University, Aachen, Germany 4) Center for Computational Life Sciences (CCLS), RWTH Aachen University, Aachen, Germany
• Marina Wolf-El Houari - 1) Institute of Neurophysiology, Uniklinik RWTH Aachen University, Aachen, Germany
• Ralf Hausmann - 2) Scientific Center for Neuropathic Pain Aachen SCN-AACHEN, Uniklinik RWTH Aachen University, Aachen, Germany 5) Institute of Clinical Pharmacology, Uniklinik RWTH Aachen University, Aachen, Germany
• Angelika Lampert - 1) Institute of Neurophysiology, Uniklinik RWTH Aachen University, Aachen, Germany 2) Scientific Center for Neuropathic Pain Aachen SCN-AACHEN, Uniklinik RWTH Aachen University, Aachen, Germany