Heat-resistant action potentials require TTX-resistant sodium channels Na(V)1.8 and Na(V)1.9

Damage-sensing nociceptors in the skin provide an indispensable protective function thanks to their specialized ability to detect and transmit hot temperatures that would block or inflict irreversible damage in other mammalian neurons. Here we show that the exceptional capacity of skin C-fiber nociceptors to encode noxiously hot temperatures depends on two tetrodotoxin (TTX)-resistant sodium channel α-subunits: Na(V)1.8 and Na(V)1.9. We demonstrate that Na(V)1.9, which is commonly considered an amplifier of subthreshold depolarizations at 20°C, undergoes a large gain of function when temperatures rise to the pain threshold. We also show that this gain of function renders Na(V)1.9 capable of generating action potentials with a clear inflection point and positive overshoot. In the skin, heat-resistant nociceptors appear as two distinct types with unique and possibly specialized features: one is blocked by TTX and relies on Na(V)1.9, and the second type is insensitive to TTX and composed of both Na(V)1.8 and Na(V)1.9. Independent of rapidly gated TTX-sensitive Na(V) channels that form the action potential at pain threshold, Na(V)1.8 is required in all heat-resistant nociceptors to encode temperatures higher than ∼46°C, whereas Na(V)1.9 is crucial for shaping the action potential upstroke and keeping the Na(V)1.8 voltage threshold within reach.