1.A.4.2.11
TRPV6 epithelial Ca²⁺ channel (ECaC2) (forms homo- and heterotetrameric channels with TRPV5; requires the S100A10-annexin 2 complex for routing to the plasma membrane) (Hoenderop et al., 2003; van de Graaf et al., 2003). Epithelial TrpV6, but not TrpV5, is inhibited by the regulator of G-protein signaling 2 (RGS2; Q9JHX0; 211 aas) by direct binding (Schoeber et al., 2006). Calmodulin (CaM) positively affects TRPV6 activity upon Ca²⁺ binding to EF-hands 3 and 4, located in the high Ca²⁺ affinity CaM C-terminus (Lambers et al. 2004). Cyclophilin B is an accessory activating protein (Stumpf et al., 2008).  The crystal structure of rat TRPV6 at 3.25 A resolution revealed shared and unique features compared with other TRP channels (Saotome et al. 2016). Intracellular domains engage in extensive interactions to form an intracellular 'skirt' involved in allosteric modulation. In the K⁺ channel-like transmembrane domain, Ca²⁺ selectivity is determined by direct coordination of Ca²⁺ by a ring of aspartate side chains in the selectivity filter (Saotome et al. 2016).  Replacing Gly-516 within the cytosolic S4-S5 linker (conserved in all TRP channel proteins) by ser forces the channels into an open conformation, thereby enhancing constitutive Ca²⁺ entry and preventing inactivation (Hofmann et al. 2016). Tetrameric ion channels have either swapped or non-swapped arrangements of the S1-S4 and pore domains. Singh et al. 2017 showed that mutations in the transmembrane domain can result in conversion from a domain-swapped to the non-swapped fold. These results raise the possibility that a single ion channel subtype can fold into either arrangement in vivo, affecting its function in normal or disease states. Cryo-EM structures of human TRPV6 in the open and closed states shows that the channel selectivity filter adopts similar conformations in both states, consistent with its explicit role in ion permeation. The iris-like channel opening is accompanied by an alpha-to-pi-helical transition in the pore-lining transmembrane helix S6 at an alanine hinge just below the selectivity filter. As a result of this transition, the S6 helices bend and rotate, exposing different residues to the ion channel pore in the open and closed states (McGoldrick et al. 2017). TRPV6 is an epithelial Ca²⁺-selective channel associated with transient neonatal hyperparathyroidism (TNHP), an autosomal-recessive disease caused by TRPV6 mutations that affect maternal-fetal calcium transport (Suzuki et al. 2018). TRPV6 mediates calcium uptake in epithelia, and its expression increases in numerous types of cancer while inhibitors suppress tumor growth. Singh et al. 2018 presented crystal and cryo-EM structures of human and rat TRPV6 bound to 2-aminoethoxydiphenyl borate (2-APB), a TRPV6 inhibitor and modulator of numerous TRP channels. 2-APB binds to TRPV6 in a pocket formed by the cytoplasmic half of the S1-S4 transmembrane helix bundle. 2-APB induces TRPV6 channel closure by modulating protein-lipid interactions. The 2-APB binding site may be present in other members of vanilloid subfamily TRP channels. The crystal structure has been determined (see 30299652 and Yelshanskaya et al. 2020). Novel mutations in TRPV6 give rise to the spectrum of transient neonatal hyperparathyroidism (Suzuki et al. 2020). TRPV6) plays roles in calcium absorption in epithelia and bone and is involved in human diseases including vitamin-D deficiency, osteoporosis, and cancer. Cai et al. 2020 showed that the TRPV6 intramolecular S4-S5 linker to the C-terminal TRP helix (L/C) and N-terminal pre-S1 helix to TRP helix (N/C) interactions, mediated by Arg470:Trp593 and Trp321:Ile597 bonding, respectively, are autoinhibitory and are required for maintaining TRPV6 at basal states. Disruption of either interaction by mutations or blocking peptides activates TRPV6. The N/C interaction depends on the L/C interaction but not inversely. Three cationic residues in S5 or the C terminus are involved in binding PIP2 to suppress both interactions, thereby activating TRPV6 (Cai et al. 2020). The biochemistry and pathophysiology of the Transient Potential Receptor Vanilloid 6 (TRPV6) calcium channelhave been reviewed (Walker and Vuister 2023).