Understanding the physiological role of Na_V1.9: Challenges and opportunities for pain modulation

Voltage-activated Na⁺ (Na_V) channels are crucial contributors to rapid electrical signaling in the human body. As such, they are among the most targeted membrane proteins by clinical therapeutics and natural toxins. Several of the nine mammalian Na_V channel subtypes play a documented role in pain or other sensory processes such as itch, touch, and smell. While causal relationships between these subtypes and biological function have been extensively described, the physiological role of Na_V1.9 is less understood. Yet, mutations in Na_V1.9 can cause striking disease phenotypes related to sensory perception such as loss or gain of pain and chronic itch. Here, we explore our current knowledge of the mechanisms by which Na_V1.9 may contribute to pain and elaborate on the challenges associated with establishing links between experimental conditions and human disease. This review also discusses the lack of comprehensive insights into Na_V1.9-specific pharmacology, an unfortunate situation since modulatory compounds may have tremendous potential in the clinic to treat pain or as precision tools to examine the extent of Na_V1.9 participation in sensory perception processes.