摘要：SummaryTransient receptor potential vanilloid 6 (TRPV6), a calcium-selective channel possessing six transmembrane domains (S1-S6) and intracellular N and C termini, plays crucial roles in calcium absorption in epithelia and bone and is involved in human diseases including vitamin-D deficiency, osteoporosis, and cancer. The TRPV6 function and regulation remain poorly understood. Here we show that the TRPV6 intramolecular S4-S5 linker to 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 reversely. Three cationic residues in S5 or C terminus are involved in binding PIP2 to suppress both interactions thereby activating TRPV6. This study reveals “PIP2 - intramolecular interactions” regulatory mechanism of TRPV6 activation-autoinhibition, which will help elucidating the corresponding mechanisms in other TRP channels.Graphical AbstractDisplay OmittedHighlights•The R470:W593 and W321:I597 residue pairs mediate the L/C and N/C interactions in TRPV6•The L/C and N/C interactions are inhibitory for the TRPV6 function•PIP2 binds to cationic residues in the S5 helix and C terminus of TRPV6•PIP2 activates TRPV6 by disrupting the L/C and N/C interactionsBiochemistry; Neuroscience
