Walther-Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, Munich 80336, Germany.
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, IL 61605.
Proc Natl Acad Sci U S A. 2019 Mar 5;116(10):4706-4715. doi: 10.1073/pnas.1810633116. Epub 2019 Feb 15.
Zn, Mg, and Ca 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 and animals with a global "kinase-dead" point mutation in the gene. The TRPM7 channel reconstituted in lipid bilayers displayed a similar permeability to Zn and Mg Consistently, we found that endogenous TRPM7 regulates the total content of Zn and Mg in cultured cells. Unexpectedly, genetic inactivation of intestinal rather than kidney TRPM7 caused profound deficiencies specifically of Zn, Mg, and Ca 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 Zn and Mg 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.
锌、镁和钙是多种代谢过程和信号通路所必需的重要矿物质。因此，需要不同类别的阳离子选择性通道和转运体以特定于细胞的方式严格控制单个金属在细胞中的水平。然而，对于这些必需矿物质的生物体平衡的机制知之甚少。在此，我们确定了通道激酶 TRPM7 对于生物体矿物质动态平衡的核心和不可或缺的作用。通过对 TRPM7 的单通道分析、与在 和动物中具有肾脏和肠道限制性缺失突变的细胞表型以及具有基因中“激酶缺失”点突变的动物的代谢谱分析来评估 TRPM7 的功能。在脂质双层中重建的 TRPM7 通道对 Zn 和 Mg 的通透性相似。一致地，我们发现内源性 TRPM7 调节培养细胞中 Zn 和 Mg 的总含量。出乎意料的是，肠道而不是肾脏 TRPM7 的遗传失活导致生物体水平的 Zn、Mg 和 Ca 严重缺乏，这种情况与出生后早期的生长和存活不相容。相比之下，TRPM7 激酶活性的全局缺失并不影响矿物质动态平衡，这强调了 TRPM7 通道活性的重要性。最后，膳食 Zn 和 Mg 的强化显著延长了缺乏肠道 TRPM7 的后代的存活。因此，二价阳离子的生物体平衡严重依赖于一个共同的守门员，即肠道 TRPM7 通道。
