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首页> 外文期刊>Journal of Cellular Physiology >ATP depletion inhibits the endocytosis of ClC-2.
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ATP depletion inhibits the endocytosis of ClC-2.

机译：ATP耗竭抑制ClC-2的内吞作用。

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摘要

The chloride channel, ClC-2 is expressed ubiquitously and participates in multiple physiological processes. In particular, ClC-2 has been implicated in the regulation of neuronal chloride ion homeostasis and mutations in ClC-2 are associated with idiopathic generalized epilepsy. Despite the physiological and pathophysiological significance of this channel, its regulation remains incompletely understood. The functional expression of ClC-2 at the cell surface has been shown to be enhanced by depletion of cellular ATP, implicating its possible role in cellular energy sensing. In the present study, biochemical assays of cell surface expression suggest that this gain of function reflects, in part, an increase in channel number due to the reduction in ClC-2 internalization by endocytosis. Cell surface expression of the disease-causing mutant: G715E, thought to lack wild-type nucleotide binding affinity, is similarly affected, suggesting that ATP-depletion modifies the function of proteins in the endocytic pathway rather than ClC-2 directly. Using a combination of immunofluorescence and biochemical studies, we confirmed that ClC-2 is internalized via dynamin-dependent endocytosis and that the change in surface expression evoked by ATP depletion is partially mimicked by inhibition of dynamin function using a dynamin dominant-negative mutant (DynK44A). Furthermore, trafficking via the early endosomal compartment occurs in part through rab5-associated vesicles and recycling of ClC-2 to the cell surface occurs through a rab11 dependent pathway. In summary, we have determined that the internalization of ClC-2 by endocytosis is inhibited by metabolic stress, highlighting the importance for understanding the molecular mechanisms mediating the endosomal trafficking of this channel.
机译：氯通道,ClC-2表示无所不在地和参与多个生理过程。涉及神经的调节氯离子稳态,在ClC-2突变与特发性全身性相关联癫痫。这个通道的病理生理意义,其监管仍不完全理解。在细胞的功能表达ClC-2表面已被证明是增强了损耗的细胞ATP,暗示其在细胞能量感应可能的作用。本研究、生化检测细胞表面表达式表明,获得的功能在某种程度上反映了通道数量的增加由于减少ClC-2内化内吞作用。致病突变:G715E,认为缺乏野生型核苷酸结合亲和力,同样受到影响,这表明ATP-depletion修改功能的蛋白质内吞作用的途径而不是直接ClC-2。用免疫荧光和生化研究中,我们证实ClC-2通过dynamin-dependent内化的内吞作用诱发表面表达的变化通过ATP耗竭部分模仿使用dynamin dynamin功能的抑制显性负突变(DynK44A)。通过早期endosomal舱贩卖发生在通过rab5-associated囊泡和回收的ClC-2细胞表面发生通过rab11相关的通路。已经确定,ClC-2的内化通过内吞作用是抑制代谢压力,强调理解的重要性分子机制调解endosomal走私渠道。

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