TY - JOUR
T1 - Deletion or inhibition of prolyl oligopeptidase blocks lithium-induced phosphorylation of GSK3b and Akt by activation of protein phosphatase 2A
AU - Myöhänen, Timo T.
AU - Mertens, Freke
AU - Norrbacka, Susanna
AU - Cui, Hengjing
N1 - Funding Information:
This study was supported by grants from Academy of Finland (grant 318327), Jane and Aatos Erkko Foundation and Sigrid Juselius Foundation to TTM. Funding bodies did not participate in the study design nor in the collection, analysis and interpretation of data nor in writing of the report.
Publisher Copyright:
© 2021 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
KW - Cell Line, Tumor
KW - Glycogen Synthase Kinase 3 beta/metabolism
KW - HEK293 Cells
KW - Humans
KW - Lithium/pharmacology
KW - Okadaic Acid/pharmacology
KW - Phosphorylation/drug effects
KW - Proline/analogs & derivatives
KW - Prolyl Oligopeptidases/antagonists & inhibitors
KW - Protein Phosphatase 2/antagonists & inhibitors
KW - Proto-Oncogene Proteins c-akt/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85110983094&partnerID=8YFLogxK
U2 - 10.1111/bcpt.13632
DO - 10.1111/bcpt.13632
M3 - Article
C2 - 34196102
AN - SCOPUS:85110983094
SN - 1742-7835
VL - 129
SP - 287
EP - 296
JO - Basic and Clinical Pharmacology and Toxicology
JF - Basic and Clinical Pharmacology and Toxicology
IS - 4
ER -