Palmitoylation regulates cellular distribution of and transmembrane Ca flux through TrpM7

Gao, X. et al. (2022) Palmitoylation regulates cellular distribution of and transmembrane Ca flux through TrpM7. Cell Calcium, 106, 102639. (doi: 10.1016/j.ceca.2022.102639) (PMID:36027648)

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Abstract

The bifunctional cation channel/kinase TrpM7 is ubiquitously expressed and regulates embryonic development and pathogenesis of several common diseases. The TrpM7 integral membrane ion channel domain regulates transmembrane movement of divalent cations, and its kinase domain controls gene expression via histone phosphorylation. Mechanisms regulating TrpM7 are elusive. It exists in two populations in the cell: at the cell surface where it controls divalent cation fluxes, and in intracellular vesicles where it controls zinc uptake and release. Here we report that TrpM7 is palmitoylated at a cluster of cysteines at the C terminal end of its Trp domain. Palmitoylation controls the exit of TrpM7 from the endoplasmic reticulum and the distribution of TrpM7 between cell surface and intracellular pools. Using the Retention Using Selective Hooks (RUSH) system, we demonstrate that palmitoylated TrpM7 traffics from the Golgi to the surface membrane whereas non-palmitoylated TrpM7 is sequestered in intracellular vesicles. We identify the Golgi-resident enzyme zDHHC17 and surface membrane-resident enzyme zDHHC5 as responsible for palmitoylating TrpM7 and find that TrpM7-mediated transmembrane calcium uptake is significantly reduced when TrpM7 is not palmitoylated. The closely related channel/kinase TrpM6 is also palmitoylated on the C terminal side of its Trp domain. Our findings demonstrate that palmitoylation controls ion channel activity of TrpM7 and that TrpM7 trafficking is dependent on its palmitoylation. We define a new mechanism for post translational modification and regulation of TrpM7 and other Trps.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Rios, Dr Francisco and Samji, Dr Sheon and Fuller, Professor Will and Kuo, Dr Chien-Wen and Wypijewski, Dr Krzysztof and Gao, Miss Xing and De Lucca Camargo, Ms Livia and Main, Miss Alice and Gok, Mr Caglar and Brown, Miss Elaine and Touyz, Professor Rhian
Authors: Gao, X., Kuo, C.-W., Main, A., Brown, E., Rios, F. J., De Lucca Camargo, L., Mary, S., Wypijewski, K., Gök, C., Touyz, R. M., and Fuller, W.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
Journal Name:Cell Calcium
Publisher:Elsevier
ISSN:0143-4160
ISSN (Online):1532-1991
Published Online:17 August 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Cell Calcium 106: 102639
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
303370The role of NCX1 palmitoylation in cardiac functionWilliam FullerBritish Heart Foundation (BHF)SP/16/3/32317CAMS - Cardiovascular Science
305409Inhibitory G protein S-acylation as a therapeutic target in heart failureWilliam FullerBritish Heart Foundation (BHF)PG/19/5/34150CAMS - Cardiovascular Science
304319Palmitoylation of the L-Type Ca Channel Pore-Forming SubunitWilliam FullerBritish Heart Foundation (BHF)PG/18/60/33957CAMS - Cardiovascular Science
303944BHF Centre of ExcellenceColin BerryBritish Heart Foundation (BHF)RE/18/6/34217CAMS - Cardiovascular Science