Bakowski Daniel, Parekh Anant B
Department of Physiology, Anatomy, and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, United Kingdom.
Curr Biol. 2007 Jun 19;17(12):1076-81. doi: 10.1016/j.cub.2007.05.041.
A rise in cytosolic Ca(2+) concentration is used as a key activation signal in virtually all animal cells, where it triggers a range of responses, including neurotransmitter release, muscle contraction, and cell growth and proliferation. A major route for Ca(2+) influx is through store-operated Ca(2+) channels. One important intracellular target for Ca(2+) entry through store-operated channels is the mitochondrion, which increases aerobic metabolism and ATP production after Ca(2+) uptake. Here, we reveal a novel feedback pathway whereby pyruvic acid, a critical rate-limiting substrate for mitochondrial respiration, increases store-operated entry by reducing inactivation of the channels. Importantly, the effects of pyruvic acid are manifest at physiologically relevant concentrations and membrane potentials. The reduction in the inactivation of calcium release-activated calcium (CRAC) channels by pyruvate is highly specific in that it is not mimicked by other intermediary metabolic acids, does not require its metabolism, is independent of its Ca(2+) buffering action, and does not involve mitochondrial Ca(2+) uptake or ATP production. These results reveal a new and direct link between intermediary metabolism and ion-channel gating and identify pyruvate as a potential signaling messenger linking energy demand to calcium-channel function.
胞质Ca(2+)浓度的升高在几乎所有动物细胞中都被用作关键的激活信号，它能引发一系列反应，包括神经递质释放、肌肉收缩以及细胞生长和增殖。Ca(2+)内流的一条主要途径是通过储存操纵性Ca(2+)通道。通过储存操纵性通道进入细胞的Ca(2+)的一个重要细胞内靶点是线粒体，线粒体在摄取Ca(2+)后会增加有氧代谢和ATP生成。在此，我们揭示了一条新的反馈途径，即丙酮酸（线粒体呼吸的关键限速底物）通过减少通道失活来增加储存操纵性内流。重要的是，丙酮酸的作用在生理相关浓度和膜电位下即可显现。丙酮酸对钙释放激活钙（CRAC）通道失活的减少具有高度特异性，因为其他中间代谢酸无法模拟这种作用，不需要其代谢，与其Ca(2+)缓冲作用无关，也不涉及线粒体Ca(2+)摄取或ATP生成。这些结果揭示了中间代谢与离子通道门控之间一种新的直接联系，并确定丙酮酸是一种潜在的信号信使，将能量需求与钙通道功能联系起来。
