Enhanced trafficking of an inherited erythromelalgia Na(V)1.7 mutant channel at a physiological temperature.

Gain-of-function mutations which enhance activation of Na(V)1.7, a widely expressed sodium channel in nociceptors, cause human pain disorders including inherited erythromelalgia (IEM). IEM is characterized by attacks of burning pain in distal extremities triggered by warmth, with cooling of affected limbs providing temporary relief. We investigated the behaviour of the IEM-linked L858F mutant Na(V)1.7 channel at physiological normal skin temperature (NST, 33-35 °C) in IB4-negative DRG sensory neurons known to include thermosensors. Using voltage-clamp recordings at NST we found that the Na(V)1.7-L858F mutant channel shows the characteristic hyperpolarizing shift in activation as has been previously found in recordings at room temperature, and that the current density of the L858F channels is significantly larger than that of WT channels. Using a live-cell optical pulse-chase imaging methodology at NST we observed that accelerated forward-trafficking significantly increases membrane insertion of mutant channels in IB4(-) neurons. Current-clamp recordings at NST show increased firing of IB4(-) neurons that express the L858F mutant channel, consistent with increased trafficking of the channel at this physiological temperature. Our findings identify enhanced trafficking and membrane insertion of the L858F mutant channels at normal skin temperature in IB4(-) neurons as an additional mechanism underlying IEM-related neuronal hyperexcitability.