Deciphering structural bases of TRP channel inhibition as foundations for the design of new drugs

Any physical or mental activity involves ion channels. Ion channels are also associated with numerous human diseases, including those caused by mutations (channelopathies). Many drugs, including local anaesthetics, antianxiety agents and sedatives, target ion channels. However, highly efficient and selective drugs are missing for many ion channels due to our limited knowledge about their molecular mechanisms of regulation. I am particular interested in transient receptor potential (TRP) vanilloid subfamily (TRPV) channels. These polymodal sensory transducers respond to chemicals, temperature, mechanical stress and membrane voltage and are involved in vision, taste, olfaction, hearing, touch, thermal perception and nociception. In my proposed research project, I focus on two (patho-)physiologically important members of this family, TRPV3 and TRPV6.The calcium-selective channel TRPV6 plays a central role in calcium uptake in epithelial tissues. A classified oncochannel, TRPV6 is overexpressed in various types of human cancer cells, including breast, prostate, colon, ovarian, thyroid, endometrial, and leukaemia cancer cells. It appears that the central role of TRPV6 in cancer is to impair Ca2+ homeostasis by stimulating Ca2+ entry into the cell. Correspondingly, inhibitors of TRPV6-mediated calcium uptake are urgently needed for the treatment of TRPV6-rich tumours. I also study the thermo-sensitive channel TRPV3 which is activated by heat and several natural compounds like camphor, thymol, carvacrol, eugenol, and cannabinol. TRPV3 is predominantly expressed in skin keratinocytes and implicated in cutaneous sensation, including thermo-sensation, nociception and itch, in addition to maintenance of the skin barrier, wound healing, and hair growth. The dysfunction of TRPV3 channels, often a result of genetic mutations, is associated with numerous human skin diseases including a genodermatosis known as Olmsted syndrome, atopic dermatitis, and rosacea. Furthermore, overexpression of TRPV3 is implicated in the development and progression of colorectal and lung cancer.I aim to solve structures of TRPV3 and TRPV6 in complex with different agonists, antagonists, allosteric modulators, and ion channel blockers. Identified binding sites will be tested by site-directed mutagenesis and functional recordings. Molecular models derived from the combined structural and functional approaches will serve as templates for the design of more selective and efficacious drugs targeting inflammatory skin conditions, itch, pain, and cancer.