Hot and cool findings on sodium channels’ temperature sensitivity
Despite the fact that the normal body temperature hovers around 37°C, most electrophysiological studies on ion channel function are conducted at room temperature, typically ranging from 18°C to 25°C. While such a temperature is absolutely physiological for some channels (such as those located at nerve endings in the skin), it is certainly not the case for others (i.e., ion channels in the heart). Given that temperature affects multiple cellular processes, understanding ion channels in their true physiological context is crucial, as it can offer new insights into developing treatments for ion channel-related disorders.
In a recent comprehensive study, Kriegeskorte et al. delved into examining the role of temperature on voltage-gated sodium channels (Nav), which are critical players in excitable tissues. They specifically studied how Nav subtypes Nav1.3, Nav1.5, Nav1.6, and Nav1.7 (as well as two Nav1.7 mutations linked to specific inherited pain syndromes) function under varying temperature conditions: 15°C, 25°C, and 35°C.
The researchers discovered that an increase in temperature led to a shift in Nav activation toward more hyperpolarized potentials, which essentially makes cells more excitable. These findings could offer insights into phenomena like fever-induced seizures or heart arrhythmias. On the flip side, certain pain-related mutations showed that their effects were amplified either by warmth (in the case of Inherited Erythromelalgia) or by cooling (in the case of Paroxysmal Extreme Pain Disorder), possibly explaining why individuals with these conditions are triggered by specific temperature ranges.
Interestingly, the study also suggested that increased temperatures could accelerate the opening kinetics of Nav channels, further enhancing cellular excitability at elevated temperatures – a potentially detrimental outcome for patients with temperature-sensitive conditions.
But one of the most intriguing aspects of this study was the spotlight on Nav1.3’s special sensitivity to cooling. Compared to other subtypes, Nav1.3 showed an eight-fold increase in persistent current and four times slower inactivation at cooler temperatures. This makes Nav1.3 a very interesting candidate for further research, especially considering its overexpression following nerve injuries, indicating a potential role in cold allodynia.
As for methodology, the study capitalized on the automated patch-clamp system SyncroPatch 384, making it feasible to conduct a high number of experiments at varied temperatures and thereby increasing the reliability of their findings. Nowadays, automated patch-clamp systems can perform high-throughput electrophysiological experiments at temperatures ranging from 10°C up to 60°C (in case of the Nanion’s Patchliner). This makes experiments at varied temperatures significantly simpler compared to manual patch-clamp.
In summary, the study highlights the importance of considering temperature as a regulator for channel gating, as well as its impact on cellular excitability and disease phenotypes.
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