Empson R M, Galione A
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
J Biol Chem. 1997 Aug 22;272(34):20967-70. doi: 10.1074/jbc.272.34.20967.
Ca2+ release from intracellular stores can be activated in neurons by influx of Ca2+ through voltage-gated Ca2+ channels. This process, called Ca2+-induced Ca2+ release, relies on the properties of the ryanodine receptor and represents a mechanism by which Ca2+ influx during neuronal activity can be amplified into large intracellular Ca2+ signals. In a differentiated neuroblastoma cell line, we show that caffeine, a pharmacological activator of the ryanodine receptor, released Ca2+ from intracellular stores in a Ca2+-dependent and ryanodine-sensitive manner. The pyridine nucleotide, cyclic ADP-ribose, thought to be an endogenous modulator of ryanodine receptors also amplified Ca2+-induced Ca2+ release in these neurons. Cyclic ADP-ribose enhanced the total cytoplasmic Ca2+ levels during controlled Ca2+ influx through voltage gated channels, in a concentration-dependent and ryanodine-sensitive manner and also increased the sensitivity with which a small amount of Ca2+ influx could trigger additional release from the ryanodine-sensitive intracellular Ca2+ stores. Single cell imaging showed that following the Ca2+ influx, cyclic ADP-ribose enhanced the spatial spread of the Ca2+ signal from the edge of the cell into its center. These powerful actions suggest a role for cyclic ADP-ribose in the functional coupling of neuronal depolarization, Ca2+ entry, and global intracellular Ca2+ signaling.
通过电压门控钙通道流入细胞的钙离子可激活神经元细胞内钙库中的钙离子释放。这一过程称为钙诱导的钙释放，依赖于兰尼碱受体的特性，代表了一种机制，通过该机制，神经元活动期间的钙离子内流可被放大为细胞内大的钙离子信号。在一种分化的神经母细胞瘤细胞系中，我们发现咖啡因作为兰尼碱受体的药理学激活剂，以钙离子依赖且对兰尼碱敏感的方式从细胞内钙库中释放钙离子。吡啶核苷酸环二磷酸腺苷核糖被认为是兰尼碱受体的内源性调节剂，它也能放大这些神经元中钙诱导的钙释放。环二磷酸腺苷核糖在通过电压门控通道的可控钙离子内流过程中，以浓度依赖且对兰尼碱敏感的方式提高了细胞质中总的钙离子水平，并且还增加了少量钙离子内流触发兰尼碱敏感的细胞内钙库额外释放的敏感性。单细胞成像显示，在钙离子内流后，环二磷酸腺苷核糖增强了钙离子信号从细胞边缘向细胞中心的空间扩散。这些强大的作用表明环二磷酸腺苷核糖在神经元去极化、钙离子内流和整体细胞内钙离子信号传导的功能偶联中发挥作用。
