Phiel C J, Klein P S
Department of Medicine and Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104. USA.
Annu Rev Pharmacol Toxicol. 2001;41:789-813. doi: 10.1146/annurev.pharmtox.41.1.789.
Lithium is highly effective in the treatment of bipolar disorder and also has multiple effects on embryonic development, glycogen synthesis, hematopoiesis, and other processes. However, the mechanism of lithium action is still unclear. A number of enzymes have been proposed as potential targets of lithium action, including inositol monophosphatase, a family of structurally related phosphomonoesterases, and the protein kinase glycogen synthase kinase-3. These potential targets are widely expressed, require metal ions for catalysis, and are generally inhibited by lithium in an uncompetitive manner, most likely by displacing a divalent cation. Thus, the challenge is to determine which target, if any, is responsible for a given response to lithium in cells. Comparison of lithium effects with genetic disruption of putative target molecules has helped to validate these targets, and the use of alternative inhibitors of a given target can also lend strong support for or against a proposed mechanism of lithium action. In this review, lithium sensitive enzymes are discussed, and a number of criteria are proposed to evaluate which of these enzymes are involved in the response to lithium in a given setting.
锂在双相情感障碍的治疗中非常有效，并且对胚胎发育、糖原合成、造血及其他过程也有多种作用。然而，锂的作用机制仍不清楚。许多酶被认为是锂作用的潜在靶点，包括肌醇单磷酸酶、一族结构相关的磷酸单酯酶以及蛋白激酶糖原合酶激酶-3。这些潜在靶点广泛表达，催化作用需要金属离子，并且通常以非竞争性方式被锂抑制，最有可能是通过取代二价阳离子。因此，挑战在于确定在细胞中对锂的特定反应究竟是由哪个靶点（如果有的话）介导的。将锂的作用与假定靶点分子的基因敲除效应进行比较有助于验证这些靶点，并且使用给定靶点的替代抑制剂也能为所提出的锂作用机制提供有力的支持或反驳。在这篇综述中，讨论了对锂敏感的酶，并提出了一些标准来评估在特定情况下这些酶中哪些参与了对锂的反应。
