Cold and warmth intensify pain-linked sodium channel gating effects and persistent currents

Sophia Kriegeskorte, Raya Bott, Martin Hampl, Alon Korngreen, Ralf Hausmann, Angelika Lampert

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Voltage-gated sodium channels (Nav) are key players in excitable tissues with the capability to generate and propagate action potentials. Mutations in the genes encoding Navs can lead to severe inherited diseases, and some of these so-called channelopathies show temperature-sensitive phenotypes, for example, paramyotonia congenita, Brugada syndrome, febrile seizure syndromes, and inherited pain syndromes like erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). Nevertheless, most investigations of mutation-induced gating effects have been conducted at room temperature, and thus the role of cooling or warming in channelopathies remains poorly understood. Here, we investigated the temperature sensitivity of four Nav subtypes: Nav1.3, Nav1.5, Nav1.6, and Nav1.7, and two mutations in Nav1.7 causing IEM (Nav1.7/L823R) and PEPD (Nav1.7/I1461T) expressed in cells of the human embryonic kidney cell line using an automated patch clamp system. Our experiments at 15°C, 25°C, and 35°C revealed a shift of the voltage dependence of activation to more hyperpolarized potentials with increasing temperature for all investigated subtypes. Nav1.3 exhibited strongly slowed inactivation kinetics compared with the other subtypes that resulted in enhanced persistent current, especially at 15°C, indicating a possible role in cold-induced hyperexcitability. Impaired fast inactivation of Nav1.7/I1461T was significantly enhanced by a cooling temperature of 15°C. The subtype-specific modulation as well as the intensified mutation-induced gating changes stress the importance to consider temperature as a regulator for channel gating and its impact on cellular excitability as well as disease phenotypes.

Original languageEnglish
Article numbere202213312
JournalJournal of General Physiology
Volume155
Issue number9
DOIs
StatePublished - 4 Sep 2023

Bibliographical note

Publisher Copyright:
© 2023 Kriegeskorte et al.

Funding

This work was supported by the 2020 SyncroPatch384i award by Nanion Technologies GmbH, Munich, Germany to A. Lampert and R. Hausmann. This study was funded by grants from the Interdisciplinary Centre for Clinical Research within the Faculty of Medicine at the RWTH Aachen University (IZKF TN1-1/IA 532001 and TN1-5/IA 532005) and by the Deutsche Forschungsgemeinschaft (German Research Foundation LA 2740/3–1, 363055819/GRK2415 Mechanobiology of 3D epithelial tissues [ME3T]; 368482240/GRK2416, MultiSenses-MultiScales).

FundersFunder number
Nanion Technologies GmbH
Deutsche ForschungsgemeinschaftLA 2740/3–1, 368482240/GRK2416, 363055819/GRK2415
RWTH Aachen UniversityIZKF TN1-1/IA 532001, TN1-5/IA 532005
Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg

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