Lithium has been used for the treatment of mood disorders for decades though the molecular mechanism of its therapeutic action and intracellular targets remain furtive. We report that neurotropic agent Li⁺ binds to the neuronal calcium sensor, Downstream Regulatory Element Antagonist Modulator (DREAM), with an equilibrium dissociation constant of 34 ± 4 μM and impacts DREAM structural and dynamic properties in a similar manner as observed for its physiological ligand, Ca²⁺. Results of fluorescence spectroscopy and molecular dynamics are consistent with Li⁺ binding at EF-hands. In the Li⁺ bound form, DREAM association to peptides mimicking DREAM binding sites in a voltage-gated potassium channel is enhanced compared to the apoprotein, whereas DREAM affinity for the presenilin binding site, helix-9, is impeded. These results suggest that DREAM and possibly other members of the neuronal calcium sensor family belong to Li⁺ intracellular targets and interactions between Li⁺ and NCS provide a molecular basis for Li⁺ neuroprotective action.

中文翻译：

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神经元钙传感器下游调节元件拮抗剂调节剂中的EF手展示了Li +的亚毫摩尔亲和力：Li +治疗的新前景。

锂已被用于治疗情绪障碍数十年，尽管其治疗作用的分子机制和细胞内靶标仍然是暂时的。我们报告说，促神经药Li ⁺结合到神经元钙传感器下游调节元素拮抗剂调节剂（DREAM），平衡解离常数为34±4μM，并以与观察其生理配体相似的方式影响DREAM结构和动态特性，Ca ²⁺。荧光光谱和分子动力学的结果与EF手的Li ⁺结合一致。在李⁺与载脂蛋白相比，在结合形式上，DREAM与模拟电压门控钾通道中DREAM结合位点的肽的缔合得到增强，而DREAM对早老素结合位点helix-9的亲和力受到阻碍。这些结果表明，DREAM和神经钙传感器家族的其他成员可能属于Li ⁺细胞内靶标，并且Li ⁺和NCS之间的相互作用为Li ⁺神经保护作用提供了分子基础。