Schlecker Christina, Boehmerle Wolfgang, Jeromin Andreas, DeGray Brenda, Varshney Anurag, Sharma Yogendra, Szigeti-Buck Klara, Ehrlich Barbara E
Department of Pharmacology, Yale University, New Haven, Connecticut 06520-8066, USA.
J Clin Invest. 2006 Jun;116(6):1668-74. doi: 10.1172/JCI22466. Epub 2006 May 11.
Regulation and dysregulation of intracellular calcium (Ca2+) signaling via the inositol 1,4,5-trisphosphate receptor (InsP3R) has been linked to many cellular processes and pathological conditions. In the present study, addition of neuronal calcium sensor-1 (NCS-1), a high-affinity, low-capacity, calcium-binding protein, to purified InsP3R type 1 (InsP3R1) increased the channel activity in both a calcium-dependent and -independent manner. In intact cells, enhanced expression of NCS-1 resulted in increased intracellular calcium release upon stimulation of the phosphoinositide signaling pathway. To determine whether InsP3R1/NCS-1 interaction could be functionally relevant in bipolar disorders, conditions in which NCS-1 is highly expressed, we tested the effect of lithium, a salt widely used for treatment of bipolar disorders. Lithium inhibited the enhancing effect of NCS-1 on InsP3R1 function, suggesting that InsP3R1/NCS-1 interaction is an essential component of the pathomechanism of bipolar disorder.
通过肌醇1,4,5 - 三磷酸受体(InsP3R)对细胞内钙(Ca2+)信号传导的调节和失调与许多细胞过程和病理状况有关。在本研究中,将神经元钙传感器-1(NCS-1,一种高亲和力、低容量的钙结合蛋白)添加到纯化的1型InsP3R(InsP3R1)中,以钙依赖性和非依赖性方式增加了通道活性。在完整细胞中,NCS-1表达增强导致磷酸肌醇信号通路受刺激后细胞内钙释放增加。为了确定InsP3R1/NCS-1相互作用在双相情感障碍(NCS-1高表达的疾病状态)中是否具有功能相关性,我们测试了锂(一种广泛用于治疗双相情感障碍的盐)的作用。锂抑制了NCS-1对InsP3R1功能的增强作用,表明InsP3R1/NCS-1相互作用是双相情感障碍发病机制的重要组成部分。