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首页> 美国卫生研究院文献>Cell Regulation >Ionic milieu controls the compartment-specific activation of pro-opiomelanocortin processing in AtT-20 cells.
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Ionic milieu controls the compartment-specific activation of pro-opiomelanocortin processing in AtT-20 cells.

机译：离子环境可控制AtT-20细胞中前黑素皮质素加工过程的区室特异性激活。

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Newly synthesized prohormones and their processing enzymes transit through the same compartments before being packaged into regulated secretory granules. Despite this coordinated intracellular transport, prohormone processing does not occur until late in the secretory pathway. In the mouse pituitary AtT-20 cell line, conversion of pro-opiomelanocortin (POMC) to mature adrenocorticotropic hormone involves the prohormone convertase PC1. The mechanism by which this proteolytic processing is restricted to late secretory compartments is unknown; PC1 activity could be regulated by compartment-specific activators/inhibitors, or through changes in the ionic milieu that influence its activity. By arresting transport in a semi-intact cell system, we have addressed whether metabolically labeled POMC trapped in early secretory compartments can be induced to undergo conversion if the ionic milieu in these compartments is experimentally manipulated. Prolonged incubation of labeled POMC trapped in the endoplasmic reticulum or Golgi/trans-Golgi network did not result in processing, thereby supporting the theory that processing is normally a post-Golgi/trans-Golgi network event. However, acidification of these compartments allowed effective processing of POMC to the intermediate and mature forms. The observed processing increased sharply at a pH below 6.0 and required millimolar calcium, regardless of the compartment in which labeled POMC resided. These conditions also resulted in the coordinate conversion of PC1 from the 84/87 kDa into the 74-kDa and 66-kDa forms. We propose that POMC processing is predominantly restricted to acidifying secretory granules, and that a change in pH within these granules is both necessary and sufficient to activate POMC processing.
机译：新合成的激素原及其加工酶在包装成受调节的分泌性颗粒之前，先经过相同的区室。尽管有这种协调的细胞内运输，但是激素激素的处理直到分泌途径的后期才发生。在小鼠垂体AtT-20细胞系中，促视神经黑皮质素（POMC）向成熟的促肾上腺皮质激素的转化涉及到激素原转化酶PC1。这种蛋白水解过程仅限于晚期分泌区室的机制尚不清楚； PC1的活性可以通过区室特异性激活剂/抑制剂或通过影响其活性的离子环境的变化来调节。通过阻止在半完整细胞系统中的运输，我们已经解决了如果实验性地控制了这些隔室中的离子环境，是否可以诱使捕获在早期分泌隔室中的新陈代谢标记的POMC发生转化。捕获在内质网或高尔基/反高尔基网络中的标记POMC的长时间孵育不会导致加工，因此支持了加工通常是后高尔基/反高尔基网络事件的理论。然而，这些隔室的酸化允许将POMC有效地加工成中间形式和成熟形式。观察到的过程在pH值低于6.0时急剧增加，并且需要毫摩尔钙，而与标记的POMC所在的隔室无关。这些条件还导致PC1从84/87 kDa坐标转换为74 kDa和66 kDa形式。我们提出，POMC加工主要限于酸化分泌颗粒，而这些颗粒中pH的变化对于激活POMC加工既是必要的，又是足够的。

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