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

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. Summary Activation of the sodium channel subtypes Nav1.3, Nav1.5, Nav1.6, and Nav1.7 and two pain linked mutations is alleviated by warmth. Cooler temperatures, on the other hand, strongly enhance persistent currents of Nav1.3. The impaired fast inactivation of the pain-linked Nav1.7/I1461T mutation is further impaired by cooling, mimicking clinical findings.