Tmc6, also known as EVER1, is a membrane protein whose functions are being increasingly understood. It is highly expressed in dorsal root ganglion (DRG) neurons and functions as a Gαq-coupled G protein-coupled receptor (GPCR)-like receptor to sense noxious heat. It also forms a heterotrimeric complex with TMC8 and CIB1, and is associated with the pre-malignant skin disease epidermodysplasia verruciformis (EV) [1,2].

In Tmc6-deficient mice, there is a substantial impairment in noxious heat sensation, while cold, warmth, touch, and mechanical pain perception remain normal. Disrupting the interaction between Tmc6 and Gαq, genetically ablating Gαq, or blocking Gαq-coupled GPCR signaling can replicate this phenotype. Noxious heat-induced intracellular Ca2+ release from the endoplasmic reticulum of DRG neurons is largely reduced when ablating Tmc6. Additionally, deletion of Tmc6 in DRG neurons hyperpolarizes the resting membrane potential, inhibits neuronal excitability, and alleviates heat and mechanical hyperalgesia in chronic pain, suggesting its potential as a target for chronic pain treatment [1,3].

In conclusion, Tmc6 plays a crucial role in noxious heat sensation via Gαq signaling and is involved in the modulation of neuronal excitability related to pain. The gene knockout mouse models have been instrumental in revealing its function in these processes, and its association with EV also indicates its importance in understanding the pathogenesis of this skin disease.

References:

1. Zhang, Chen, Tong, Fang, Zhou, Bin, Wang, Yan-Qing, Han, Qingjian. 2024. TMC6 functions as a GPCR-like receptor to sense noxious heat via Gαq signaling. In Cell discovery, 10, 66. doi:10.1038/s41421-024-00678-9. https://pubmed.ncbi.nlm.nih.gov/38886367/

2. Wu, Chuan-Jin, Li, Xing, Sommers, Connie L, Griffith, Andrew J, Samelson, Lawrence E. 2020. Expression of a TMC6-TMC8-CIB1 heterotrimeric complex in lymphocytes is regulated by each of the components. In The Journal of biological chemistry, 295, 16086-16099. doi:10.1074/jbc.RA120.013045. https://pubmed.ncbi.nlm.nih.gov/32917726/

3. An, Yating, Hu, Jingyi, Hao, Han, Zhang, Hailin, Du, Xiaona. 2024. The transmembrane channel-like 6 (TMC6) in primary sensory neurons involving thermal sensation via modulating M channels. In Frontiers in pharmacology, 15, 1330167. doi:10.3389/fphar.2024.1330167. https://pubmed.ncbi.nlm.nih.gov/38440182/