CNNM proteins selectively bind to the TRPM7 channel to stimulate divalent cation entry into cells

Magnesium is essential for cellular life, but how it is homeostatically controlled still remains poorly understood. Here, we report that members of CNNM family, which have been controversially implicated in both cellular Mg2+ influx and efflux, selectively bind to the TRPM7 channel to stimulate diva...

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Bibliographic Details
Published in:	PLoS biology Vol. 19; no. 12; p. e3001496
Main Authors:	Bai, Zhiyong, Feng, Jianlin, Franken, Gijs A C, Al'Saadi, Namariq, Cai, Na, Yu, Albert S, Lou, Liping, Komiya, Yuko, Hoenderop, Joost G J, de Baaij, Jeroen H F, Yue, Lixia, Runnels, Loren W
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 20-12-2021 Public Library of Science (PLoS)
Subjects:	Analysis Biology and Life Sciences Cancer Cation Transport Proteins - metabolism Cation Transport Proteins - physiology Cations Cations, Divalent - metabolism Cell Line, Tumor Cell surface Cyclins - metabolism Cyclins - physiology Divalent cations Efflux Experiments Gene expression HEK293 Cells Homeostasis Humans Identification and classification Ion channels Kinases Magnesium Magnesium - metabolism Mass spectrometry Medicine and Health Sciences Membrane proteins Mutation Patch-Clamp Techniques Physical Sciences Physiology Properties Protein expression Protein Serine-Threonine Kinases - metabolism Protein Serine-Threonine Kinases - physiology Proteins Research and Analysis Methods Scientific imaging Short Reports Transient receptor potential proteins TRPM Cation Channels - genetics TRPM Cation Channels - metabolism TRPM Cation Channels - physiology United States Netherlands Iraq
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Summary:	Magnesium is essential for cellular life, but how it is homeostatically controlled still remains poorly understood. Here, we report that members of CNNM family, which have been controversially implicated in both cellular Mg2+ influx and efflux, selectively bind to the TRPM7 channel to stimulate divalent cation entry into cells. Coexpression of CNNMs with the channel markedly increased uptake of divalent cations, which is prevented by an inactivating mutation to the channel's pore. Knockout (KO) of TRPM7 in cells or application of the TRPM7 channel inhibitor NS8593 also interfered with CNNM-stimulated divalent cation uptake. Conversely, KO of CNNM3 and CNNM4 in HEK-293 cells significantly reduced TRPM7-mediated divalent cation entry, without affecting TRPM7 protein expression or its cell surface levels. Furthermore, we found that cellular overexpression of phosphatases of regenerating liver (PRLs), known CNNMs binding partners, stimulated TRPM7-dependent divalent cation entry and that CNNMs were required for this activity. Whole-cell electrophysiological recordings demonstrated that deletion of CNNM3 and CNNM4 from HEK-293 cells interfered with heterologously expressed and native TRPM7 channel function. We conclude that CNNMs employ the TRPM7 channel to mediate divalent cation influx and that CNNMs also possess separate TRPM7-independent Mg2+ efflux activities that contribute to CNNMs' control of cellular Mg2+ homeostasis.
Bibliography:	new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The authors have declared that no competing interests exist.
ISSN:	1545-7885 1544-9173 1545-7885
DOI:	10.1371/journal.pbio.3001496