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Deletion or inhibition of prolyl oligopeptidase blocks lithium‐induced phosphorylation of GSK3b and Akt by activation of protein phosphatase 2A
Author(s) -
Myöhänen Timo T.,
Mertens Freke,
Norrbacka Susanna,
Cui Hengjing
Publication year - 2021
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.13632
Subject(s) - gsk3b , protein kinase b , protein phosphatase 2 , phosphorylation , gsk 3 , glycogen synthase , lithium (medication) , phosphatase , chemistry , pi3k/akt/mtor pathway , oligopeptidase , biochemistry , signal transduction , biology , endocrinology , enzyme
Abstract 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 3 ) 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.