Autoinhibition of TRPV6 Channel and Regulation by PIP2

Ruiqi Cai; Xiong Liu; Rui Zhang; Laura Hofmann; Wang Zheng; Md Ruhul Amin; Lingyun Wang; Qiaolin Hu; Ji-Bin Peng; Marek Michalak; Veit Flockerzi; Declan W Ali; Xing-Zhen Chen; Jingfeng Tang

doi:10.1016/j.isci.2020.101444

Autoinhibition of TRPV6 Channel and Regulation by PIP2

iScience. 2020 Aug 8;23(9):101444. doi: 10.1016/j.isci.2020.101444. eCollection 2020 Sep 25.

Authors

Ruiqi Cai^{1

2}, Xiong Liu², Rui Zhang¹, Laura Hofmann³, Wang Zheng², Md Ruhul Amin⁴, Lingyun Wang⁵, Qiaolin Hu², Ji-Bin Peng⁵, Marek Michalak⁶, Veit Flockerzi³, Declan W Ali⁴, Xing-Zhen Chen², Jingfeng Tang¹

Affiliations

¹ National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, Hubei 430068, China.
² Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
³ Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, 66421 Homburg, Germany.
⁴ Department of Biological Sciences, Biological Sciences Building, University of Alberta, T6G 2E9 Edmonton, AB, Canada.
⁵ Division of Nephrology, Department of Medicine, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
⁶ Membrane Protein Disease Research Group, Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.

Abstract

Transient 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.

Keywords: Biochemistry; Neuroscience.

Grants and funding

R01 DK104924/DK/NIDDK NIH HHS/United States