Orai1 Boosts SK3 Channel Activation.
Orai1 Boosts SK3 Channel Activation.
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DOI：
10.3390/cancers13246357
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发表时间：
2021-12-17
期刊：
影响因子：
5.2
通讯作者：
Derler I
中科院分区：
文献类型：
--
作者：
Tiffner A;Hopl V;Schober R;Sallinger M;Grabmayr H;Höglinger C;Fahrner M;Lunz V;Maltan L;Frischauf I;Krivic D;Bhardwaj R;Schindl R;Hediger MA;Derler I
乳腺癌、结肠癌和前列腺癌约占癌症病例的三分之一和癌症死亡的五分之一。在分子水平上，癌症发展的一个原因是细胞蛋白质的功能障碍或改变的共调节。在这项研究中，我们专注于离子通道的共同调节，特别是突出的Ca 2+离子通道Orai 1和Ca 2+激活的K+离子通道SK 3。最近有报道称，它们的相互作用促进了乳腺癌和结肠癌细胞的生长，但它们共同调节的分子决定因素仍然难以捉摸。在这项研究中，我们开始描述它们的相互作用和因此需要的关键区域。此外，我们发现前列腺癌细胞的功能也受到Ca ~（2+）和Ca ~（2+）敏感性K ~+通道相互作用的控制。我们的研究结果提供了对这些离子通道的共同调节的更好理解，这可以在未来用于开发新的治疗方法。据报道，SK 3（一种Ca 2+敏感性K+离子通道）与Orai 1（一种Ca 2+离子通道）的相互作用会增加细胞溶质Ca 2+水平，从而引发乳腺癌和结肠癌细胞的增殖，尽管迄今为止分子机制仍然难以捉摸。我们在目前的研究中表明，通过异源蛋白表达，Orai 1可以增强SK 3 K+电流，除了组成型结合钙调素（CaM）。在降低SK 3 K+渗透的低胞质Ca 2+水平下，共表达的Orai 1增强SK 3电流。SK 3和Orai 1的这种正反馈机制是通过它们的紧密共定位实现的。值得注意的是，我们发现由于过度表达的CaM突变体导致的SK 3通道活性的丧失可以通过Orai 1恢复，可能是通过其与SK 3-CaM结合位点的相互作用。映射Orai 1内的相互作用位点，我们确定了胞质链和孔残基是与SK 3的功能通信的关键。此外，STIM 1在SK 3-Orai 1调节中具有双峰作用。在生理离子条件下，STIM 1能够通过显著降低它们的共定位来阻碍SK 3-Orai 1相互作用。强制STIM 1-Orai 1活性和相关的Ca 2+内流促进SK 3 K+电流。还在人前列腺癌细胞系LNCaP中确定了Orai 1促进内源性SK 3通道的动态调节。
Breast, colon, and prostate cancer account for about a third of cancer cases and a fifth of cancer deaths. At the molecular level, one reason for the development of cancer is the dysfunction or altered co-regulation of cellular proteins. In this study, we focused on the co-regulation of ion channels, specifically the prominent Ca2+ ion channel Orai1 and the Ca2+ activated K+ ion channel SK3. It has recently been reported that their interplay promotes the growth of breast and colon cancer cells, but the molecular determinants for their co-regulation have remained elusive. In this study, we set out to characterize their interplay and the crucial regions therefore required. Moreover, we found that the function of prostate cancer cells is also controlled by the interplay of Ca2+ and the Ca2+ sensitive K+ channels. Our findings provide a better understanding of the co-regulation of these ion channels, which could be used in the future for the development of novel therapeutics. The interplay of SK3, a Ca2+ sensitive K+ ion channel, with Orai1, a Ca2+ ion channel, has been reported to increase cytosolic Ca2+ levels, thereby triggering proliferation of breast and colon cancer cells, although a molecular mechanism has remained elusive to date. We show in the current study, via heterologous protein expression, that Orai1 can enhance SK3 K+ currents, in addition to constitutively bound calmodulin (CaM). At low cytosolic Ca2+ levels that decrease SK3 K+ permeation, co-expressed Orai1 potentiates SK3 currents. This positive feedback mechanism of SK3 and Orai1 is enabled by their close co-localization. Remarkably, we discovered that loss of SK3 channel activity due to overexpressed CaM mutants could be restored by Orai1, likely via its interplay with the SK3–CaM binding site. Mapping for interaction sites within Orai1, we identified that the cytosolic strands and pore residues are critical for a functional communication with SK3. Moreover, STIM1 has a bimodal role in SK3–Orai1 regulation. Under physiological ionic conditions, STIM1 is able to impede SK3–Orai1 interplay by significantly decreasing their co-localization. Forced STIM1–Orai1 activity and associated Ca2+ influx promote SK3 K+ currents. The dynamic regulation of Orai1 to boost endogenous SK3 channels was also determined in the human prostate cancer cell line LNCaP.
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影响因子：
4
作者：
Butorac, Carmen;Muik, Martin;Romanin, Christoph
通讯作者：
Romanin, Christoph
影响因子：
5.5
作者：
Derler, Isabella;Hofbauer, Michael;Romanin, Christoph
通讯作者：
Romanin, Christoph
DOI：
10.1073/pnas.0608358103
发表时间：
2006-11-07
影响因子：
11.1
作者：
Baba, Yoshihiro;Hayashit, Kenji;Kurosaki, Tomohiro
通讯作者：
Kurosaki, Tomohiro
影响因子：
--
作者：
Dragoni S;Turin I;Laforenza U;Potenza DM;Bottino C;Glasnov TN;Prestia M;Ferulli F;Saitta A;Mosca A;Guerra G;Rosti V;Luinetti O;Ganini C;Porta C;Pedrazzoli P;Tanzi F;Montagna D;Moccia F
通讯作者：
Moccia F
DOI：
10.1074/jbc.m111.227546
发表时间：
2011-09-09
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Bergsmann J;Derler I;Muik M;Frischauf I;Fahrner M;Pollheimer P;Schwarzinger C;Gruber HJ;Groschner K;Romanin C
通讯作者：
Romanin C