Wasserman Michael J, Corson Timothy W, Sibony David, Cooke Robert G, Parikh Sagar V, Pennefather Peter S, Li Peter P, Warsh Jerry J
Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada.
Neuropsychopharmacology. 2004 Apr;29(4):759-69. doi: 10.1038/sj.npp.1300400.
Elevated basal intracellular calcium (Ca(2+)) levels (Ca(2+)) in B lymphoblast cell lines (BLCLs) from bipolar I disorder (BD-I) patients implicate altered Ca(2+) homeostasis in this illness. Chronic lithium treatment affects key proteins modulating intracellular Ca(2+) signaling. Thus, we sought to determine if chronic exposure to therapeutic lithium concentrations also modifies intracellular Ca(2+) homeostasis in this surrogate cellular model of signal transduction disturbances in BD. BLCLs from BD-I (N=26) and healthy subjects (N=17) were regrown from frozen stock and incubated with 0.75 mM lithium or vehicle for 24 h (acute) or 7 days (chronic). Ca(2+), lysophosphatidic acid (LPA)-stimulated Ca(2+) mobilization (Ca(2+)), and thapsigargin-induced store-operated Ca(2+) entry (SOCE) were determined using ratiometric fluorometry with Fura-2. Compared with vehicle, chronic lithium exposure resulted in significantly higher Ca(2+) (F=8.47; p=0.006) in BLCLs from BD-I and healthy subjects. However, peak LPA-stimulated Ca(2+) and SOCE were significantly reduced (F=11.1, p=0.002 and F=8.36, p=0.007, respectively). Acute lithium exposure did not significantly affect measured parameters. In summary, the effect of chronic lithium to elevate Ca(2+) in BLCLs while attenuating both receptor-stimulated and SOCE components of intracellular Ca(2+) mobilization in BLCLs suggests that modulation of intracellular Ca(2+) homeostasis may be important to the therapeutic action of lithium.
双相 I 型障碍（BD-I）患者的 B 淋巴母细胞系（BLCLs）中基础细胞内钙（Ca(2+)）水平（Ca(2+)）升高，这表明该疾病中钙（Ca(2+)）稳态发生了改变。慢性锂治疗会影响调节细胞内 Ca(2+)信号传导的关键蛋白。因此，我们试图确定在 BD 信号转导障碍的这种替代细胞模型中，长期暴露于治疗浓度的锂是否也会改变细胞内 Ca(2+)稳态。从冻存株中复苏 BD-I 患者（N = 26）和健康受试者（N = 17）的 BLCLs，并与 0.75 mM 锂或赋形剂孵育 24 小时（急性）或 7 天（慢性）。使用 Fura-2 通过比率荧光法测定Ca(2+)、溶血磷脂酸（LPA）刺激的 Ca(2+)动员（Ca(2+)）和毒胡萝卜素诱导的钙库操纵性 Ca(2+)内流（SOCE）。与赋形剂相比，长期锂暴露导致 BD-I 患者和健康受试者的 BLCLs 中Ca(2+)显著升高（F = 8.47；p = 0.006）。然而，LPA 刺激的Ca(2+)峰值和 SOCE 显著降低（分别为 F = 11.1，p = 0.002 和 F = 8.36，p = 0.007）。急性锂暴露对所测参数无显著影响。总之，慢性锂在升高 BLCLs 中Ca(2+)的同时，减弱细胞内 Ca(2+)动员的受体刺激和 SOCE 成分，这表明细胞内 Ca(2+)稳态的调节可能对锂的治疗作用很重要。
