Essential role of Orai1 store-operated calcium channels in lactation
Essential role of Orai1 store-operated calcium channels in lactation
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DOI：
10.1073/pnas.1502264112
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发表时间：
2015-05-05
影响因子：
11.1
通讯作者：
Putney, James W., Jr.
中科院分区：
文献类型：
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作者：
Davis, Felicity M.;Janoshazi, Agnes;Putney, James W., Jr.
哺乳动物的特征是通过哺乳来喂养新生儿。然而，尽管对哺乳的神经控制进行了大量研究，但对哺乳期间乳腺上皮细胞产生和排出乳汁的信号机制的理解仍然很大程度上未知。在这里，我们证明了一个商店操作的钙通道亚基，Orai1，需要最佳的钙转运到牛奶和牛奶喷射。使用一种新的，3D成像策略，我们可视化活催产素诱导的肺泡单位收缩在乳腺中，我们表明，在这个模型中，牛奶喷射的方式脉动收缩这些肺泡单位。在Orai1基因敲除小鼠的乳腺中，这些收缩不频繁且协调性差。我们发现，催产素也诱导一个大的瞬时释放存储的Ca2+在乳腺肌上皮细胞缓慢，不规则的Ca2+振荡。这些振荡，而不是最初的Ca2+瞬变，是专门由Orai 1介导的，是绝对需要的牛奶喷射和幼崽的生存，观察重新定义的信号过程负责牛奶喷射。这些发现清楚地表明，Ca2+不仅是哺乳动物营养富集的底物，而且是支撑乳腺肺泡单位收缩的时空信号事件的主调节器。Orai1依赖性Ca2+振荡可能代表其他分泌上皮（如汗腺）的肌上皮细胞中的保守语言，可能揭示其他Orai1通道病，包括无汗症（无法出汗）。
The nourishment of neonates by nursing is the defining characteristic of mammals. However, despite considerable research into the neural control of lactation, an understanding of the signaling mechanisms underlying the production and expulsion of milk by mammary epithelial cells during lactation remains largely unknown. Here we demonstrate that a store-operated Ca2+ channel subunit, Orai1, is required for both optimal Ca2+ transport into milk and for milk ejection. Using a novel, 3D imaging strategy, we visualized live oxytocin-induced alveolar unit contractions in the mammary gland, and we demonstrated that in this model milk is ejected by way of pulsatile contractions of these alveolar units. In mammary glands of Orai1 knockout mice, these contractions are infrequent and poorly coordinated. We reveal that oxytocin also induces a large transient release of stored Ca2+ in mammary myoepithelial cells followed by slow, irregular Ca2+ oscillations. These oscillations, and not the initial Ca2+ transient, are mediated exclusively by Orai1 and are absolutely required for milk ejection and pup survival, an observation that redefines the signaling processes responsible for milk ejection. These findings clearly demonstrate that Ca2+ is not just a substrate for nutritional enrichment in mammals but is also a master regulator of the spatiotemporal signaling events underpinning mammary alveolar unit contraction. Orai1-dependent Ca2+ oscillations may represent a conserved language in myoepithelial cells of other secretory epithelia, such as sweat glands, potentially shedding light on other Orai1 channelopathies, including anhidrosis (an inability to sweat).