1.A.4.2.8
The noxious heat (>52°C)-sensitive vanilloid-like receptor cation selective channel, TRPV2. Ca²⁺-dependent desensitization of TRPV2 channels is mediated by hydrolysis of phosphatidylinositol 4,5-bisphosphate (Mercado et al., 2010).  Deleting the first N-terminal 74 residues preceding the ankyrin repeat domain (ARD) shows a key role for this region in targeting the protein to the membrane. Co-translational insertion of the membrane-embedded region occurs with the TM1-TM4 and TM5-TM6 regions assembling as independent folding domains. ARD is not required for TM domain insertion into the membrane (Doñate-Macian et al. 2015).  The TRPV2 structure has been solved at 4 Å resolution by cryoEM (Zubcevic et al. 2016). Formation of a physical complex between mouse TRPV2 (GRC) and the mouse RGA protein promotes cell surface expression of TRPV2 (Stokes et al. 2005). The role of Ca²⁺ infllux via TRPV1 in cell death and survival related to cancer has been evaluated (Zhai et al. 2020). A helix-turn-helix motif for high temperature dependence of TRPV2 has been identified (Liu and Qin 2021). As noted above, TRPV2 is a ligand-operated temperature sensor. Zhang et al. 2022 combined calcium imaging and patch-clamp electrophysiology with cryo-EM to explore how TRPV2 activity is modulated by the phytocannabinoid Δ⁹-tetrahydrocannabiorcol (C16) and by probenecid. C16 and probenecid act in concert to stimulate TRPV2 responses including histamine release from mast cells. Each ligand causes distinct conformational changes in TRPV2. Although the binding for probenecid remains elusive, C16 associates within the vanilloid pocket. As such, the C16 binding location is distinct from that of cannabidiol, partially overlapping with the binding site of the TRPV2 inhibitor piperlongumine (Zhang et al. 2022). The cation-permeable TRPV2 channel is important for cardiac and immune cell function (Gochman et al. 2023). Cannabidiol (CBD), a non-psychoactive cannabinoid of clinical relevance, is one of the few molecules known to activate TRPV2. Using the patch-clamp technique, Gochman et al. 2023 discovered that CBD can sensitize current responses of the rat TRPV2 channel to the synthetic agonist 2-aminoethoxydiphenyl borate (2-APB) by over two orders of magnitude, without sensitizing channels to activation by moderate (40°C) heat. Using cryo-EM, Gochman et al. 2023 uncovered a new small-molecule binding site in the pore domain of rTRPV2 in addition to a nearby CBD site.  Intrinsically disordered regions in TRPV2 mediate protein-protein interactions (Sanganna Gari et al. 2023).  Sitagliptin eye drops prevent the impairment of retinal neurovascular unit in a Trpv2^+/- rat model (Ramos et al. 2024).