Transmembrane channel-like protein 6 (TMC6)

Transmembrane channel-like protein 6 (TMC6) is an integral membrane protein with 10 predicted transmembrane domains and large N- and C-terminal domains on opposite sides of the plasma membrane[1][5]. It is a member of the TMC family of proteins, most homologous to TMC8. TMC6 localizes primarily to the endoplasmic reticulum but can also be found at the plasma membrane and in other subcellular localizations, including the nuclear membrane and Golgi apparatus[4][5]. TMC6, together with TMC8, forms a complex with zinc transporter 1 (ZnT-1/SLC30A1) that regulates zinc fluxes in cells, particularly in keratinocytes and lymphocytes[4][5][6]. Mutations in TMC6 are a cause of epidermodysplasia verruciformis (EV), a rare skin disorder associated with increased susceptibility to cutaneous human papillomavirus (HPV) infection and a high risk of developing skin cancers[4][5]. Beyond its role in zinc homeostasis and immune defense, recent research demonstrates that TMC6 acts as a non-classical GPCR-like receptor in sensory neurons, involved in thermal pain sensation. It modulates the activity of the neuronal M channel (KCNQ2/KCNQ3), affecting membrane excitability and response to noxious heat[1][3][5]. Loss of TMC6 increases intracellular zinc, which can activate the M channel, leading to reduced neuronal excitability and altered heat sensitivity—making it a potential target for modulating chronic pain and nociception[3]. No approved drugs are currently known to directly target TMC6, nor are there established biomarkers or mechanisms of action outside its molecular and physiological interactions as described above. However, therapeutic approaches targeting TMC6 or its pathways may have implications in HPV susceptibility, cancer prevention, and chronic pain modulation. Notably, safety concerns would relate to its essential skin barrier and immune protective roles[5][3][4].

Other names

EVER1EVIN1LAK-4PEpidermodysplasia verruciformis protein 1Protein LAK-4EV1TNRC6C-AS1Transmembrane channel-like protein 6TNRC6C antisense RNA 1