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首页> 外文期刊>Molecular and Cellular Biology >The Phosphatidylinositol 3-Phosphate Phosphatase Myotubularin- Related Protein 6 (MTMR6) Is a Negative Regulator of the Ca2+-Activated K+ Channel KCa3.1
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The Phosphatidylinositol 3-Phosphate Phosphatase Myotubularin- Related Protein 6 (MTMR6) Is a Negative Regulator of the Ca2+-Activated K+ Channel KCa3.1

机译：磷酸肌醇3-磷酸磷酸酶肌管蛋白相关蛋白6（MTMR6）是Ca2 +激活的K +通道KCa3.1的负调节剂。

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Myotubularins (MTMs) belong to a large subfamily of phosphatases that dephosphorylate the 3′ position of phosphatidylinositol 3-phosphate [PI(3)P] and PI(3,5)P2. MTM1 is mutated in X-linked myotubular myopathy, and MTMR2 and MTMR13 are mutated in Charcot-Marie-Tooth syndrome. However, little is known about the general mechanism(s) whereby MTMs are regulated or the specific biological processes regulated by the different MTMs. We identified a Ca2+-activated K channel, KCa3.1 (also known as KCa4, IKCa1, hIK1, or SK4), that specifically interacts with the MTMR6 subfamily of MTMs via coiled coil (CC) domains on both proteins. Overexpression of MTMR6 inhibited KCa3.1 channel activity, and this inhibition required MTMR6's CC and phosphatase domains. This inhibition is specific; MTM1, a closely related MTM, did not inhibit KCa3.1. However, a chimeric MTM1 in which the MTM1 CC domain was swapped for the MTMR6 CC domain inhibited KCa3.1, indicating that MTM CC domains are sufficient to confer target specificity. KCa3.1 was also inhibited by the PI(3) kinase inhibitors LY294002 and wortmannin, and this inhibition was rescued by the addition of PI(3)P, but not other phosphoinositides, to the patch pipette solution. PI(3)P also rescued the inhibition of KCa3.1 by MTMR6 overexpression. These data, when taken together, indicate that KCa3.1 is regulated by PI(3)P and that MTMR6 inhibits KCa3.1 by dephosphorylating the 3′ position of PI(3)P, possibly leading to decreased PI(3)P in lipid microdomains adjacent to KCa3.1. KCa3.1 plays important roles in controlling proliferation by T cells, vascular smooth muscle cells, and some cancer cell lines. Thus, our findings not only provide unique insights into the regulation of KCa3.1 channel activity but also raise the possibility that MTMs play important roles in the negative regulation of T cells and in conditions associated with pathological cell proliferation, such as cancer and atherosclerosis.
机译：肌管蛋白（MTM）属于磷酸酶的一个大亚家族，可将磷脂酰肌醇3-磷酸[PI（3）P]和PI（3,5）P 2 的3'位置去磷酸化。 X连锁肌管肌病中 MTM1 发生突变，而Charcot-Marie-Tooth综合征中 MTMR2 和 MTMR13 发生突变。但是，人们对MTM调控或由不同MTM调控的特定生物学过程的一般机制知之甚少。我们确定了一个Ca 2 + 激活的K通道，即K Ca 3.1（也称为KCa4，IKCa1，hIK1或SK4），该通道专门与MTMR6的亚家族相互作用MTM通过两种蛋白质上的卷曲螺旋（CC）域进行连接。 MTMR6的过表达抑制了K Ca 3.1通道的活性，这种抑制作用需要MTMR6的CC和磷酸酶结构域。这种抑制作用是特异性的。 MTM1是密切相关的MTM，它不抑制K Ca 3.1。然而，其中MTM1 CC结构域被交换为MTMR6 CC结构域的嵌合MTM1抑制了K Ca 3.1，表明MTM CC结构域足以赋予靶标特异性。 K Ca 3.1也被PI（3）激酶抑制剂LY294002和渥曼青霉素抑制，并且通过向贴片移液器中添加PI（3）P而不是其他磷酸肌醇来挽救这种抑制作用。 。 PI（3）P还挽救了MTMR6过表达对K Ca 3.1的抑制作用。这些数据加在一起表明K Ca 3.1受PI（3）P调节，而MTMR6通过去磷酸化PI（3）P抑制K Ca 3.1（ 3）P，可能导致与K Ca 3.1相邻的脂质微区PI（3）P降低。 K Ca 3.1在控制T细胞，血管平滑肌细胞和某些癌细胞系的增殖中起重要作用。因此，我们的发现不仅提供了对K Ca 3.1通道活性调节的独特见解，而且还增加了MTM在T细胞的负调节以及与病理性细胞增殖有关的疾病中起重要作用的可能性。 ，例如癌症和动脉粥样硬化。

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