Tmc6, also known as EVER1, encodes a transmembrane protein. It functions as a Gαq -coupled G protein-coupled receptor (GPCR)-like receptor to sense noxious heat, with its intracellular C-terminal region (Ser780-Pro810) interacting with Gαq [1]. It also forms a heterotrimeric complex with TMC8 and CIB1 in lymphocytes, and mutations in Tmc6 are associated with epidermodysplasia verruciformis (EV), a disease that predisposes to human papillomavirus (HPV) infections and skin malignancies [2,3,4,6,7].

Tmc6-deficient mice display a substantial impairment in noxious heat sensation while maintaining normal perception of cold, warmth, touch, and mechanical pain [1]. Ablating Tmc6 in dorsal root ganglion (DRG) neurons hyperpolarizes the resting membrane potential, inhibits neuronal excitability, and enhances M channel function due to increased free zinc levels, alleviating heat and mechanical hyperalgesia in chronic pain [5].

In conclusion, Tmc6 is crucial for noxious heat sensation and is involved in peripheral heat nociception. Studies on Tmc6-deficient mouse models have revealed its significance in pain-related biological processes and its potential as a target for chronic pain treatment. Additionally, Tmc6 mutations are associated with EV, highlighting its role in susceptibility to HPV-related diseases [1,5].