Myöhänen Timo T, Mertens Freke, Norrbacka Susanna, Cui Hengjing
Division of Pharmacology and Pharmacotherapy/Drug Research Program, University of Helsinki, Helsinki, Finland.
Integrative Physiology and Pharmacology Unit, Institute of Biomedicine, University of Turku, Turku, Finland.
Basic Clin Pharmacol Toxicol. 2021 Oct;129(4):287-296. doi: 10.1111/bcpt.13632. Epub 2021 Jul 20.
Alterations in prolyl oligopeptidase (PREP) activity have been connected, for example, with bipolar and major depressive disorder, and several studies have reported that lack or inhibition of PREP blocks the effects of lithium on inositol 1,4,5-triphosphate (IP ) levels. However, the impact of PREP modulation on other intracellular targets of lithium, such as glycogen synthase kinase 3 beta (GSK3b) or protein kinase B (Akt), has not been studied. We recently found that PREP regulates protein phosphatase 2A (PP2A), and because GSK3b and Akt are PP2A substrates, we studied if PREP-related lithium insensitivity is dependent on PP2A. To assess this, HEK-293 and SH-SY5Y cells with PREP deletion or PREP inhibition (KYP-2047) were exposed to lithium, and thereafter, the phosphorylation levels of GSK3b and Akt were measured by Western blot. As expected, PREP deletion and inhibition blocked the lithium-induced phosphorylation on GSK3b and Akt in both cell lines. When lithium exposure was combined with okadaic acid, a PP2A inhibitor, KYP-2047 did not have effect on lithium-induced GSK3b and Akt phosphorylation. Therefore, we conclude that PREP deletion or inhibition blocks the intracellular effects of lithium on GSK3b and Akt via PP2A activation.
例如，脯氨酰寡肽酶（PREP）活性的改变与双相情感障碍和重度抑郁症有关，并且多项研究报道，PREP的缺失或抑制会阻断锂对肌醇1,4,5-三磷酸（IP）水平的影响。然而，PREP调节对锂的其他细胞内靶点，如糖原合酶激酶3β（GSK3b）或蛋白激酶B（Akt）的影响尚未得到研究。我们最近发现PREP调节蛋白磷酸酶2A（PP2A），并且由于GSK3b和Akt是PP2A的底物，我们研究了与PREP相关的锂不敏感性是否依赖于PP2A。为了评估这一点，将具有PREP缺失或PREP抑制（KYP-2047）的HEK-293和SH-SY5Y细胞暴露于锂，然后通过蛋白质印迹法测量GSK3b和Akt的磷酸化水平。正如预期的那样，PREP的缺失和抑制阻断了两种细胞系中锂诱导的GSK3b和Akt磷酸化。当锂暴露与PP2A抑制剂冈田酸联合使用时，KYP-2047对锂诱导的GSK3b和Akt磷酸化没有影响。因此，我们得出结论，PREP的缺失或抑制通过PP2A激活阻断了锂对GSK3b和Akt的细胞内作用。
