TRPM7 is the central gatekeeper of intestinal mineral absorption essential for postnatal survival
| Autor: | Camilla Recordati, Masayuki Matsushita, Attila Braun, David G. Simmons, Eleonora Zakharian, Lorenz Mittermeier, Lusine Demirkhanyan, Vladimir Chubanov, Andreas Breit, Benjamin Stadlbauer, Anne Hilgendorff, Thomas Gudermann |
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| Rok vydání: | 2019 |
| Předmět: |
inorganic chemicals
0301 basic medicine Physiology TRPM7 TRPM Cation Channels Endogeny magnesium Kidney 03 medical and health sciences Gene Knockout Techniques Mice 0302 clinical medicine medicine Animals Homeostasis Mineral absorption Kinase activity Intestinal Mucosa Mice Knockout Minerals Multidisciplinary calcium Chemistry TRP channels Point mutation zinc Transporter Biological Sciences Cell biology 030104 developmental biology medicine.anatomical_structure PNAS Plus Signal transduction 030217 neurology & neurosurgery |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 |
| Popis: | Significance Zn2+, Mg2+, and Ca2+ are the most abundant divalent metals in mammals. Different categories of cation-selective channels and transporters are thought to control the levels of individual metals in a cell-specific manner. However, the mechanisms responsible for the organismal balance of these minerals are poorly understood. Using genetic mouse models together with biophysical and biochemical analysis, we show that the channel-kinase TRPM7 is a master regulator of the organismal balance of divalent cations. TRPM7 activity is primarily required in the intestine, while TRPM7 function in the kidney—commonly thought to be essential—is expendable. Hence, against current thinking, organismal balance of multiple divalent cations predominantly relies on a common gatekeeper, TRPM7, rather than on individual specialized channels/transporters. 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. |
| Databáze: | OpenAIRE |
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