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Proc Natl Acad Sci U S A. 2019 Feb 15. pii: 201810633. doi: 10.1073/pnas.1810633116. [Epub ahead of print]

TRPM7 is the central gatekeeper of intestinal mineral absorption essential for postnatal survival.

Author information

1
Walther-Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, Munich 80336, Germany.
2
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, IL 61605.
3
Mouse and Animal Pathology Laboratory, Filarete Foundation, 20139 Milan, Italy.
4
Center for Comprehensive Developmental Care, Integrated Social Pediatric Center, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich 80337, Germany.
5
Comprehensive Pneumology Center, Munich 80337, Germany.
6
German Center for Lung Research, Munich 80337, Germany.
7
Department of Molecular and Cellular Physiology, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan.
8
Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg 97080, Germany.
9
School of Biomedical Sciences, University of Queensland, QLD 4072, Australia.
10
Walther-Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, Munich 80336, Germany; Thomas.Gudermann@lrz.uni-muenchen.de vladimir.chubanov@lrz.uni-muenchen.de.
11
Munich Heart Alliance, Munich 80336, Germany.

Abstract

Zn2+, Mg2+, and Ca2+ are essential minerals required for a plethora of metabolic processes and signaling pathways. Different categories of cation-selective channels and transporters are therefore required to tightly control the cellular levels of individual metals in a cell-specific manner. However, the mechanisms responsible for the organismal balance of these essential minerals are poorly understood. Herein, we identify a central and indispensable role of the channel-kinase TRPM7 for organismal mineral homeostasis. The function of TRPM7 was assessed by single-channel analysis of TRPM7, phenotyping of TRPM7-deficient cells in conjunction with metabolic profiling of mice carrying kidney- and intestine-restricted null mutations in Trpm7 and animals with a global "kinase-dead" point mutation in the gene. The TRPM7 channel reconstituted in lipid bilayers displayed a similar permeability to Zn2+ and Mg2+ Consistently, we found that endogenous TRPM7 regulates the total content of Zn2+ and Mg2+ in cultured cells. Unexpectedly, genetic inactivation of intestinal rather than kidney TRPM7 caused profound deficiencies specifically of Zn2+, Mg2+, and Ca2+ at the organismal level, a scenario incompatible with early postnatal growth and survival. In contrast, global ablation of TRPM7 kinase activity did not affect mineral homeostasis, reinforcing the importance of the channel activity of TRPM7. Finally, dietary Zn2+ and Mg2+ fortifications significantly extended the survival of offspring lacking intestinal TRPM7. Hence, the organismal balance of divalent cations critically relies on one common gatekeeper, the intestinal TRPM7 channel.

KEYWORDS:

TRP channels; TRPM7; calcium; magnesium; zinc

PMID:
30770447
DOI:
10.1073/pnas.1810633116
Free PMC Article

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