TRPC3, a member of the transient receptor potential (TRP) superfamily of cation channels, is a lipid-regulated, Ca2+-permeable channel that mediates essential components of the receptor evoked Ca2+ signal. The modes and mechanisms by which lipids regulate TRPC3 and other members of the TRPC channel family are not well understood. Here, we report that PI(4,5)P2 regulates TRPC3 in three independent modes. PLC-dependent hydrolysis generates diacylglycerol (DAG) that interacts with lipid-binding site 2 in the channel pore. PI(4,5)P2 interacts with lipid site 1 to inhibit TRPC3 opening and regulate access of DAG to the pore lipid site 2. PI(4,5)P2 is required for regulating pore ionic selectivity by receptor stimulation. Notably, the activation and regulation of TRPC3 by PI(4,5)P2 require recruitment of TRPC3 to the ER/PM junctions at a PI(4,5)P2-rich domain. Accordingly, we identified an FFAT site at the TRPC3 N-terminal loop within the linker helices that envelope the C-terminus pole helix. The FFAT site interacts with the ER-resident VAPB to recruit TRPC3 to the ER/PM junctions and control its receptor-mediated activation. The TRPC3’s lipid interacting sites are fully conserved in TRPC6 and TRPC7 and in part in other TRPC channels. These findings inform on multiple modes of regulation of ion channels by lipids that may be relevant to diseases affected by aberrant TRPC channel functions.
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2 May 2022
Article|
April 13 2022
TRPC3 channel gating by lipids requires localization at the ER/PM junctions defined by STIM1
Haiping Liu,
1
Epithelial Signaling and Transport Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
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Wei-Yin Lin,
1
Epithelial Signaling and Transport Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
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Spencer R. Leibow
,
Spencer R. Leibow
1
Epithelial Signaling and Transport Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
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Alexander J. Morateck
,
Alexander J. Morateck
1
Epithelial Signaling and Transport Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
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Malini Ahuja,
1
Epithelial Signaling and Transport Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
Malini Ahuja: malini.ahuja@nih.gov
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Shmuel Muallem
1
Epithelial Signaling and Transport Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
Correspondence to Shmuel Muallem: shmuel.muallem@nih.gov
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1
Epithelial Signaling and Transport Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
1
Epithelial Signaling and Transport Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
Spencer R. Leibow
1
Epithelial Signaling and Transport Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
Alexander J. Morateck
1
Epithelial Signaling and Transport Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
1
Epithelial Signaling and Transport Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
Correspondence to Shmuel Muallem: shmuel.muallem@nih.gov
Malini Ahuja: malini.ahuja@nih.gov
*
H. Liu and W.-Y. Lin are co-first authors.
Received:
July 20 2021
Revision Received:
December 08 2021
Accepted:
March 08 2022
Online Issn: 1540-8140
Print Issn: 0021-9525
Funding
Funder(s):
National Institutes of Health
- Award Id(s): NIH/NIDCR DE000735-10
This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.
2022
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Cell Biol (2022) 221 (5): e202107120.
Article history
Received:
July 20 2021
Revision Received:
December 08 2021
Accepted:
March 08 2022
Citation
Haiping Liu, Wei-Yin Lin, Spencer R. Leibow, Alexander J. Morateck, Malini Ahuja, Shmuel Muallem; TRPC3 channel gating by lipids requires localization at the ER/PM junctions defined by STIM1. J Cell Biol 2 May 2022; 221 (5): e202107120. doi: https://doi.org/10.1083/jcb.202107120
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