Modulation of Ca2+ release and Ca2+ oscillations in HeLa cells and fibroblasts by mitochondrial Ca2+ uniporter stimulation
Modulation of Ca2+ release and Ca2+ oscillations in HeLa cells and fibroblasts by mitochondrial Ca2+ uniporter stimulation
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DOI：
10.1113/jphysiol.2006.126391
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发表时间：
2007-04-01
影响因子：
5.5
通讯作者：
Alvarez, Javier
中科院分区：
文献类型：
--
作者：
Vay, Laura;Hernandez-SanMiguel, Esther;Alvarez, Javier
最近可用的线粒体Ca 2+单向转运体的激活剂允许直接测试线粒体Ca 2+摄取对细胞整体Ca 2+稳态的影响。我们在此表明，4，4 '，4'-（4-丙基-[1H]-吡唑-1，3，5-三基）三酚（PPT）或山奈酚激活线粒体Ca 2+摄取可刺激组胺诱导的内质网（ER）Ca 2+释放，如果同时用CGP 37157抑制线粒体Na+-Ca 2+交换，则这种作用增强。这表明线粒体的Ca 2+摄取和释放控制局部Ca 2+微区产生对肌醇1，4，5-三磷酸受体（InsP（3）Rs）的反馈抑制的能力。此外，线粒体控制Ca 2+从ER释放的能力允许它们调节胞质Ca 2+振荡。在组胺刺激的HeLa细胞和人成纤维细胞，PPT和山奈酚最初刺激，后来抑制振荡，虽然山奈酚通常诱导一个更长的刺激期。这两种化合物也能够诱导先前沉默的成纤维细胞中的Ca 2+振荡的产生。我们的数据表明，胞质Ca 2+振荡对线粒体Ca 2+摄取和释放的速率非常敏感，线粒体Ca 2+摄取和释放的速率精确地控制了InsP（3）Rs周围局部Ca 2+微区的大小，从而产生反馈激活或抑制Ca 2+释放的能力。
The recent availability of activators of the mitochondrial Ca2+ uniporter allows direct testing of the influence of mitochondrial Ca2+ uptake on the overall Ca2+ homeostasis of the cell. We show here that activation of mitochondrial Ca2+ uptake by 4,4',4'-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) or kaempferol stimulates histamine-induced Ca2+ release from the endoplasmic reticulum (ER) and that this effect is enhanced if the mitochondrial Na+-Ca2+ exchanger is simultaneously inhibited with CGP37157. This suggests that both Ca2+ uptake and release from mitochondria control the ability of local Ca2+ microdomains to produce feedback inhibition of inositol 1,4,5-trisphosphate receptors (InsP(3)Rs). In addition, the ability of mitochondria to control Ca2+ release from the ER allows them to modulate cytosolic Ca2+ oscillations. In histamine stimulated HeLa cells and human fibroblasts, both PPT and kaempferol initially stimulated and later inhibited oscillations, although kaempferol usually induced a more prolonged period of stimulation. Both compounds were also able to induce the generation of Ca2+ oscillations in previously silent fibroblasts. Our data suggest that cytosolic Ca2+ oscillations are exquisitely sensitive to the rates of mitochondrial Ca2+ uptake and release, which precisely control the size of the local Ca2+ microdomains around InsP(3)Rs and thus the ability to produce feedback activation or inhibition of Ca2+ release.