Heat-resistant action potentials require TTX-resistant sodium channels Na_V1.8 and Na_V1.9

Area of Science:

• Neuroscience
• Molecular Biology
• Sensory Physiology

Background:

• Skin nociceptors detect harmful stimuli, protecting the body.
• Mammalian neurons typically fail at high temperatures, but specialized nociceptors can withstand and signal heat.
• The molecular mechanisms underlying heat detection in nociceptors are not fully understood.

Purpose of the Study:

• To investigate the role of sodium channel alpha subunits in encoding noxious heat in skin C-fiber nociceptors.
• To determine the specific contributions of Na_V1.8 and Na_V1.9 to heat detection and action potential generation.

Main Methods:

• Electrophysiological recordings from skin C-fiber nociceptors.
• Utilizing tetrodotoxin (TTX) sensitivity as a distinguishing factor between nociceptor subtypes.
• Investigating the functional properties of Na_V1.9 at varying temperatures.

Main Results:

• Heat-encoding in C-fiber nociceptors relies on tetrodotoxin (TTX)-resistant sodium channels Na_V1.8 and Na_V1.9.
• Na_V1.9 exhibits a significant gain of function at noxious heat temperatures, enabling action potential generation.
• Two distinct types of heat-resistant nociceptors were identified: TTX-sensitive (Na_V1.9-dependent) and TTX-insensitive (Na_V1.8 and Na_V1.9 dependent).
• Na_V1.8 is essential for encoding temperatures above ~46°C, while Na_V1.9 shapes the action potential upstroke.

Conclusions:

• Na_V1.8 and Na_V1.9 are critical for the specialized function of heat-sensing nociceptors.
• Na_V1.9 plays a dual role, amplifying subthreshold signals at moderate temperatures and driving action potentials at noxious heat levels.
• Understanding these channels provides insight into pain perception and thermal regulation.