TRPV3 activation by different agonists accompanied by lipid dissociation from the vanilloid site
Year: 2024
Type: article
Abstract: TRPV3 represents both temperature- and ligand-activated transient receptor potential (TRP) channel. Physiologically relevant opening of TRPV3 channels by heat has been captured structurally, while opening by agonists has only been observed in structures of mutant channels. Here, we present cryo-EM structures that illuminate opening and inactivation of wild-type human TRPV3 in response to binding of two types of agonists: either the natural cannabinoid tetrahydrocannabivarin (THCV) or synthetic agonist 2-aminoethoxydiphenylborane (2-APB). We found that THCV binds to the vanilloid site, while 2-APB binds to the S1-S4 base and ARD-TMD linker sites. Despite binding to distally located sites, both agonists induce similar pore opening and cause dissociation of a lipid that occupies the vanilloid site in their absence. Our results uncover different but converging allosteric pathways through which small-molecule agonists activate TRPV3 and provide a framework for drug design and understanding the role of lipids in ion channel function.
Source: Science Advances
Institution: Columbia University
Language: English
Topic: Ion Channels and Receptors
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,500
Awards: G4689185066, Structure and Function of AMPA subtype ionotropic glutamate receptors, G6221506569, G686058816, Single-Particle Cryo-EM Characterization of AMPA Receptor Functional States, Structure and function of Transient Receptor Potential Channels, Structural and functional principles of activation and regulation of the transient receptor potential channel TRPV3.
OpenAlex ID: W4396541677