Williams R S, Eames M, Ryves W J, Viggars J, Harwood A J
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK.
EMBO J. 1999 May 17;18(10):2734-45. doi: 10.1093/emboj/18.10.2734.
The therapeutic properties of lithium ions (Li+) are well known; however, the mechanism of their action remains unclear. To investigate this problem, we have isolated Li+-resistant mutants from Dictyostelium. Here, we describe the analysis of one of these mutants. This mutant lacks the Dictyostelium prolyl oligopeptidase gene (dpoA). We have examined the relationship between dpoA and the two major biological targets of lithium: glycogen synthase kinase 3 (GSK-3) and signal transduction via inositol (1,4,5) trisphosphate (IP3). We find no evidence for an interaction with GSK-3, but instead find that loss of dpoA causes an increased concentration of IP3. The same increase in IP3 is induced in wild-type cells by a prolyl oligopeptidase (POase) inhibitor. IP3 concentrations increase via an unconventional mechanism that involves enhanced dephosphorylation of inositol (1,3,4,5,6) pentakisphosphate. Loss of DpoA activity therefore counteracts the reduction in IP3 concentration caused by Li+ treatment. Abnormal POase activity is associated with both unipolar and bipolar depression; however, the function of POase in these conditions is unclear. Our results offer a novel mechanism that links POase activity to IP3 signalling and provides further clues for the action of Li+ in the treatment of depression.
锂离子（Li+）的治疗特性广为人知；然而，其作用机制仍不清楚。为了研究这个问题，我们从盘基网柄菌中分离出了耐Li+突变体。在此，我们描述了对其中一个突变体的分析。这个突变体缺乏盘基网柄菌脯氨酰寡肽酶基因（dpoA）。我们研究了dpoA与锂的两个主要生物学靶点之间的关系：糖原合酶激酶3（GSK-3）和通过肌醇（1,4,5）三磷酸（IP3）的信号转导。我们没有发现与GSK-3相互作用的证据，而是发现dpoA的缺失导致IP3浓度增加。脯氨酰寡肽酶（POase）抑制剂在野生型细胞中也能诱导相同的IP3增加。IP3浓度通过一种非常规机制增加，该机制涉及肌醇（1,3,4,5,6）五磷酸的去磷酸化增强。因此，DpoA活性的丧失抵消了Li+处理引起的IP3浓度降低。异常的POase活性与单相和双相抑郁症都有关；然而，POase在这些情况下的功能尚不清楚。我们的结果提供了一种将POase活性与IP3信号传导联系起来的新机制，并为Li+在抑郁症治疗中的作用提供了进一步的线索。
