The coiled-coil domain of zebrafish TRPM7 regulates Mg·nucleotide sensitivity.
The coiled-coil domain of zebrafish TRPM7 regulates Mg·nucleotide sensitivity.
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DOI：
10.1038/srep33459
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发表时间：
2016-09-15
影响因子：
4.6
通讯作者：
Fleig A
中科院分区：
文献类型：
--
作者：
Jansen C;Sahni J;Suzuki S;Horgen FD;Penner R;Fleig A
TRPM 7是瞬时受体电位Melastatin离子通道家族的成员。TRPM 7是一种独特的离子通道和α-激酶的融合蛋白。尽管哺乳动物TRPM 7在生物药理学上得到了很好的表征，并且其在癌症、缺血和心血管疾病中的关键作用变得越来越明显，但转基因消融的胚胎致死性阻碍了在小鼠模型中对TRPM 7的研究。在斑马鱼中，TRPM 7（drTRPM 7）的功能丧失表现为一系列非致命的生理功能障碍。在这里，我们调查野生型drTRPM 7和多个C-末端截短突变体的调节。我们发现drTRPM 7的生物物理特性与哺乳动物TRPM 7非常相似。然而，药理学分析表明，drTRPM 7是促进，而不是抑制2-APB，和TRPM 7抑制剂waixenicin A没有影响。这让人想起人TRPM 6的药理学特征，TRPM 6是TRPM 7的姐妹通道激酶。此外，使用截断突变，我们表明，drTRPM 7的卷曲螺旋结构域参与镁（Mg）和镁·三磷酸腺苷（Mg·ATP）对通道的调节。我们建议drTRPM 7有两个蛋白质结构域，调节细胞内镁和核苷酸的抑制，和一个结构域，只与传感镁有关。
TRPM7 is a member of the Transient-Receptor-Potential Melastatin ion channel family. TRPM7 is a unique fusion protein of an ion channel and an α-kinase. Although mammalian TRPM7 is well characterized biophysically and its pivotal role in cancer, ischemia and cardiovascular disease is becoming increasingly evident, the study of TRPM7 in mouse models has been hampered by embryonic lethality of transgenic ablations. In zebrafish, functional loss of TRPM7 (drTRPM7) manifests itself in an array of non-lethal physiological malfunctions. Here, we investigate the regulation of wild type drTRPM7 and multiple C-terminal truncation mutants. We find that the biophysical properties of drTRPM7 are very similar to mammalian TRPM7. However, pharmacological profiling reveals that drTRPM7 is facilitated rather than inhibited by 2-APB, and that the TRPM7 inhibitor waixenicin A has no effect. This is reminiscent of the pharmacological profile of human TRPM6, the sister channel kinase of TRPM7. Furthermore, using truncation mutations, we show that the coiled-coil domain of drTRPM7 is involved in the channel’s regulation by magnesium (Mg) and Mg·adenosine triphosphate (Mg·ATP). We propose that drTRPM7 has two protein domains that regulate inhibition by intracellular magnesium and nucleotides, and one domain that is concerned with sensing magnesium only.
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影响因子：
2.7
作者：
Decker AR;McNeill MS;Lambert AM;Overton JD;Chen YC;Lorca RA;Johnson NA;Brockerhoff SE;Mohapatra DP;MacArthur H;Panula P;Masino MA;Runnels LW;Cornell RA
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影响因子：
56.9
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通讯作者：
Kinet, JP
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2.4
作者：
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