TRPM7 is the central gatekeeper of intestinal mineral absorption essential for postnatal survival
TRPM7 is the central gatekeeper of intestinal mineral absorption essential for postnatal survival
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DOI：
10.1073/pnas.1810633116
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发表时间：
2019-03-05
影响因子：
11.1
通讯作者：
Chubanov, Vladimir
中科院分区：
文献类型：
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作者：
Mittermeier, Lorenz;Demirkhanyan, Lusine;Chubanov, Vladimir
Zn2+、Mg2+和Ca2+是多种代谢过程和信号通路所必需的矿物质。因此，需要不同种类的阳离子选择通道和转运体以细胞特异性的方式严格控制单个金属的细胞水平。然而，负责这些必需矿物质的有机平衡的机制却知之甚少。在这里，我们确定了通道激酶TRPM7在有机矿物质稳态中的核心和不可或缺的作用。TRPM7的功能通过TRPM7的单通道分析、TRPM7缺陷细胞的表型分析以及携带肾脏和肠道限制性TRPM7零突变的小鼠和携带该基因全局“激酶死亡”点突变的动物的代谢谱来评估。在脂质双层中重构的TRPM7通道表现出与Zn2+和Mg2+相似的通透性。与此一致，我们发现内源性TRPM7调节培养细胞中Zn2+和Mg2+的总含量。出乎意料的是，肠道而非肾脏TRPM7的基因失活导致了机体水平上的严重缺陷，特别是Zn2+、Mg2+和Ca2+，这与出生后早期的生长和生存不相容。相比之下，TRPM7激酶活性的整体消融并不影响矿物质稳态，这加强了TRPM7通道活性的重要性。最后，饲粮中添加Zn2+和Mg2+显著延长了肠道缺乏TRPM7的后代的存活率。因此，二价阳离子的机体平衡严重依赖于一个共同的看门人，即肠道TRPM7通道。
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.