Bimodal Regulation of Plasmalemmal Ca2+ entry by the coupling of mitochondria and the endoplasmic reticulum

肥胖症是能量摄入过多和/或能量消耗减少的结果。能量通过基础代谢活动、肌肉活动和产热作用消耗。肾上腺素能激活棕色脂肪细胞中的脂解和解偶联蛋白，导致产热而不发生氧化磷酸化。这个过程消耗的能量是由H^+泵（电子传递链）产生的H^+跨线粒体膜的电化学电势，而H ^+泵需要TCA循环中依赖Ca^2+的代谢酶产生NADH和FADH 2。因此，这一过程受到细胞内游离Ca^2+（[Ca^2+]i）水平的强烈影响，而游离Ca ^2+受Ca^2+结合、Ca ^2+在质膜上的进入和排出、Ca^2+在线粒体和内质网（ER）中的释放和摄取的调节。我们研究了这些细胞器和质膜在调节[Ca^<2+>]I中如何相互联系，以及这些偶联如何参与大鼠棕色脂肪细胞的产热。我们的观察揭示了棕色脂肪细胞中[Ca^2+]I调节的新机制：（1）氧化磷酸化的解偶联激活质膜上依赖代谢产物的Ca^2+内流，（2）线粒体Ca^2+释放诱导内质网Ca^2+释放，（3）内质网Ca^2+耗竭通过线粒体诱导的Ca^2+释放激活部分细胞中的钙库操作的Ca^2+内流（SOC），（4）内质网Ca^2+耗竭激活线粒体Ca^2+释放。(5)这些机制被去甲肾上腺素的α-和fl-作用激活，表明在产热中的重要作用。

Obesity is the result of excess energy intake and/or decreased energy consumption. Energy is consumed by basal metabolic activity, muscle activity and thermogenesis. Adrenergic activations of lipolysis and uncoupling proteins in brown adipocytes lead to heat production without oxidative phosphorylation. The energy dissipated by this process is the H^+ electrochemical potential across the mitochondrial membrane generated by H^+ pumps, electron transfer chains, that require NADH and FADH2 produced by Ca^<2+>-dependent dehydrogeneses in TCA cycle. Thus, this process is strongly affected by the level of intracellular free Ca^<2+> ([Ca^<2+>]i), which are regulated by Ca^<2+> binding, Ca^<2+> entry and extrusion at the plasma membrane, Ca^<2+> release and uptake into, and from, mitochondria and the endoplasmic reticulum(ER). We studied how these organelles and the plasmalemma communicate with each other in regulating [Ca^<2+>]I and how these coupling are involved in thermogenesis in rat brown adipocytes. Our observations revealed new mechanisms of [Ca^<2+>]I, regulation in brown adipocytes:(1) uncoupling of oxidative phosphorylation activates a metabolite dependent Ca^<2+> entry at the plasmalemma, (2) mitochondrial Ca^<2+> release induces Ca^<2+> release from the ER, (3) Ca^<2+> depletion in the ER via mitochondria-induced Ca^<2+> release activates store-operated Ca^<2+> entry (SOC) in a fraction of cells and (4) Ca^<2+> depletion in the ER activates Ca^<2+> release from mitochondria. (5) These mechanisms are activated by the α- and fl-actions of noradrenaline, suggesting important roles in thermogenesis.