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

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 are showing 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 were 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), 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 to 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 cooling temperature to 15 °C. The subtype specific modulation as well as the intensified mutation induced gating changes stress the importance to consider temperature as regulator for channel gating and its impact on cellular excitability as well as disease phenotypes.

Biophysics of sodium channels during subthreshold depolarizationin vitroandin silico

“…When reviewing raw data, several of these outliers appeared to result of measurement artifacts, so that it might be worthwhile to amend an outlier analysis. To compensate for outliers destabilizing statistical results, usage of high-throughput, automated patch-clamp systems could also be considered, as they offer a time-efficient method to gather large data sets (Kriegeskorte et al 2023, Thompson et al 2023).…”

“…Note that computational models are simplifications of the real world and therefore must be handled cautiously, especially when model complexity suggests the opposite. For example, VGSC data is usually gathered at room temperature, and temperature dependence of VGSCs varies for each channel subtype and recorded voltages (Kriegeskorte et al 2023). Thus, most computational models published in the recent years do not account for temperature, since this would require additional experimental data and re-parametrization of the models (Almog and Korngreen 2016).…”

“…Larger studies which compare VGSC gating in the same experimental setting were focusing either on CNS VGSCs and their mutations leading e.g. to epilepsy (Thompson et al 2023), or on sensory neuron sodium channels and their temperature dependence (Kriegeskorte et al 2023).…”

Dendritic excitations govern back-propagation via a spike-rate accelerometer

“…This temperature effect could explain the difference between our results and prior measurements at room temperature of bAP propagation into distal dendrites. 10 Previously published simulations that accounted for the different temperature sensitivities of A-type KV channels and NaV channels 64,65 predicted temperature-sensitive back-propagation dynamics. 44 Electrophysiology Somatic whole-cell recordings were acquired from hippocampal CA1 pyramidal neurons using a custom upright microscope.…”