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- W4366171242 abstract "The TRPV3 channel, the dominant TRP receptor in skin, is heavily involved in skin physiology. The non-selective cation channel is highly expressed in keratinocytes and regulates epidermal barrier formation, hair follicle growth and keratinocyte-mediated inflammation while also mediating cutaneous itch and pain sensation. Gain of function mutations in the channel have been identified in severe skin diseases, such as Olmsted syndrome, demonstrating a causative role in severe itch and keratinocyte hyperproliferation. Because of this, TRPV3 has emerged as an attractive keratinocyte target for the treatment of hyperkeratosis, epidermal cancers, hair disorders, inflammation and itch/pain. Besides allosteric activation, the channel is activated by heat and high temperature. While the activation of TRPV3 has been studied at the functional level in vitro, its structural mechanisms remain unknown. Our lab performed cryogenic electron microscopy (cryo-EM) of TRPV3 in both its heat activated and wild type (WT) resting states. Activated TRPV3 was expressed via a point mutation previously described to switch the channel into its high-temperature activated state. Whole-cell patch-clamp confirmed active function of the channel prior to cryo-EM imaging. Cryo-EM structures demonstrated remarkable similarity between the heat-activated and WT-resting states. However, a structural difference was found in the segment linking the S6 and TRP box domains. This region contains the W692G gain-of-function mutation found in Olmsted syndrome, suggesting this structural feature to be mechanistically related to severe itch and hyperkeratosis. Calorimetry experiments confirmed similar heat uptake function and capacity in both channels, however, molecular dynamic simulation demonstrated greater random molecular movement in the activated channel, suggesting the structural feature predisposes the channel to greater structural instability." @default.
- W4366171242 created "2023-04-19" @default.
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- W4366171242 date "2023-05-01" @default.
- W4366171242 modified "2023-09-28" @default.
- W4366171242 title "738 Cryo-EM and molecular dynamics of TRPV3 channel in activated state reveal structural features implicated in severe itch and hyperkeratosis" @default.
- W4366171242 doi "https://doi.org/10.1016/j.jid.2023.03.747" @default.
- W4366171242 hasPublicationYear "2023" @default.
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