A1 Refereed original research article in a scientific journal

Deletion or inhibition of prolyl oligopeptidase blocks lithium-induced phosphorylation of GSK3b and Akt by activation of protein phosphatase 2A



Authors: Myöhänen Timo T, Mertens Freke, Norrbacka Susanna, Cui Hengjing

Publisher: WILEY

Publication year: 2021

Journal:: Basic and Clinical Pharmacology and Toxicology

Journal name in source: BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY

Journal acronym: BASIC CLIN PHARMACOL

Volume: 129

Issue: 4

First page : 287

Last page: 296

Number of pages: 10

ISSN: 1742-7835

DOI: https://doi.org/10.1111/bcpt.13632

Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/66608141


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 (IP3) 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.

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Last updated on 2024-26-11 at 23:11