1.A.4.2.9
The temperature (heat; >39°C)-sensitive, capsaicin-insensitive receptor cation-selective channel, TRPV3 or TRL3 (may form heterooligomers with VR1 (TRPV1; TC #1.A.4.2.1)). Incensole acetate, an incense component, elicits psychoactivity by activating TRPV3 channels in the brain (Moussaieff et al., 2008).  TRPV3 is activated by synthetic small-molecule chemicals and natural compounds from plants as well as warm temperatures. Its function is regulated by a variety of physiological factors including extracellular divalent cations and acidic pH, intracellular ATP, membrane voltage, and arachidonic acid. It shows a broad expression pattern in both neuronal and non-neuronal tissues including epidermal keratinocytes, epithelial cells in the gut, endothelial cells in blood vessels, and neurons in dorsal root ganglia and the CNS. TRPV3 null mice exhibit abnormal hair morphogenesis and compromised skin barrier function, and it may play critical roles in inflammatory skin disorders, itch, and pain sensation (Luo and Hu 2014). TRPV3 gating involves large rearrangements at the cytoplasmic inter-protomer interface, and this motion triggers coupling between cytoplasmic and transmembrane domains, priming the channel for opening (Zubcevic et al. 2019). Mutations in TRPV3 cause painful focal plantar keratoderma (Peters et al. 2020). TRPV3 is a temperature-sensitive, nonselective cation channel expressed prominently in skin keratinocytes that plays important roles in hair morphogenesis and maintenance of epidermal barrier function. Mechanisms of proton inhibition and sensitization have been discussed (Wang et al. 2021). Mechanisms of proton inhibition and sensitization of TRPV3 have been considered (Wang et al. 2021). TRPV3 is predominantly expressed in skin keratinocytes and has been implicated in cutaneous sensation and associated with numerous skin pathologies and cancers. TRPV3 is inhibited by the natural coumarin derivative osthole, an active ingredient of Cnidium monnieri, which has been used in traditional Chinese medicine for the treatment of various human diseases. Neuberger et al. 2021 presented cryo-EM structures of TRPV3 in complex with osthole, revealing two types of osthole binding sites in the transmembrane region of TRPV3 that coincide with the binding sites of agonist 2-APB. Osthole binding converts the channel pore into a previously unidentified conformation with a widely open selectivity filter and closed intracellular gate. The structures provide insight into competitive inhibition of TRPV3 by osthole (Neuberger et al. 2021). Scutellarein attenuates atopic dermatitis by selectively inhibiting TRP Vanilloid 3 (Wang et al. 2022). TRPV3 involvement in itching, heat pain, hair development, and TRPV3-related skin diseases has been reviewed (Guo et al. 2023).  Temperature-sensitive contact modes allosterically gate TRPV3 (Burns et al. 2023). More than 210 structures from more than 20 different TRP channels have been determined, and all are tetramers. TrpV3 exhibits the pore-dilation phenomenon, whereby prolonged activation leads to increased conductance, permeability to large ions and loss of rectification (Lansky et al. 2023). TRPV3 can exist in a pentameric state which is in dynamic equilibrium with the canonical tetramer through membrane diffusive protomer exchange. The pentamer population increased upon diphenylboronic anhydride (DPBA) addition, an agonist that has been shown to induce TRPV3 pore dilation with a larger pore size (Lansky et al. 2023). TRPV3 is a candidate gene for the suri phenotype in the alpaca (Pallotti et al. 2024).