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Open AccessArticle

Prolyl Oligopeptidase Regulates Dopamine Transporter Oligomerization and Phosphorylation in a PKC- and ERK-Independent Manner

1
Division of Pharmacology and Pharmacotherapy/Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E (P.O. Box 56), FI-00014 Helsinki, Finland
2
Integrative Physiology and Pharmacology Unit/Institute of Biomedicine, Faculty of Medicine, University of Turku, FI-20520 Turku, Finland
*
Author to whom correspondence should be addressed.
Academic Editor: Philippe De Deurwaerdère
Int. J. Mol. Sci. 2021, 22(4), 1777; https://doi.org/10.3390/ijms22041777
Received: 22 January 2021 / Revised: 4 February 2021 / Accepted: 5 February 2021 / Published: 10 February 2021
(This article belongs to the Special Issue Pharmacology of Neurodegenerative Diseases)
Prolyl oligopeptidase (PREP) is a serine protease that binds to alpha-synuclein (aSyn) and induces its aggregation. PREP inhibitors have been shown to have beneficial effects in Parkinson’s disease models by enhancing the clearance of aSyn aggregates and modulating striatal dopamine. Additionally, we have shown that PREP regulates phosphorylation and internalization of dopamine transporter (DAT) in mice. In this study, we clarified the mechanism behind this by using HEK-293 and PREP knock-out HEK-293 cells with DAT transfection. We tested the effects of PREP, PREP inhibition, and alpha-synuclein on PREP-related DAT regulation by using Western blot analysis and a dopamine uptake assay, and characterized the impact of PREP on protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) by using PKC assay and Western blot, respectively, as these kinases regulate DAT phosphorylation. Our results confirmed our previous findings that a lack of PREP can increase phosphorylation and internalization of DAT and decrease uptake of dopamine. PREP inhibition had a variable impact on phosphorylation of ERK dependent on the metabolic state of cells, but did not have an effect on phosphorylation or function of DAT. PREP modifications did not affect PKC activity either. Additionally, a lack of PREP elevated a DAT oligomerization that is associated with intracellular trafficking of DAT. Our results suggest that PREP-mediated phosphorylation, oligomerization, and internalization of DAT is not dependent on PKC or ERK. View Full-Text
Keywords: dopamine; serine protease; alpha-synuclein; extracellular signal-regulated kinase; protein kinase C dopamine; serine protease; alpha-synuclein; extracellular signal-regulated kinase; protein kinase C
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MDPI and ACS Style

Julku, U.H.; Jäntti, M.; Svarcbahs, R.; Myöhänen, T.T. Prolyl Oligopeptidase Regulates Dopamine Transporter Oligomerization and Phosphorylation in a PKC- and ERK-Independent Manner. Int. J. Mol. Sci. 2021, 22, 1777. https://doi.org/10.3390/ijms22041777

AMA Style

Julku UH, Jäntti M, Svarcbahs R, Myöhänen TT. Prolyl Oligopeptidase Regulates Dopamine Transporter Oligomerization and Phosphorylation in a PKC- and ERK-Independent Manner. International Journal of Molecular Sciences. 2021; 22(4):1777. https://doi.org/10.3390/ijms22041777

Chicago/Turabian Style

Julku, Ulrika H.; Jäntti, Maria; Svarcbahs, Reinis; Myöhänen, Timo T. 2021. "Prolyl Oligopeptidase Regulates Dopamine Transporter Oligomerization and Phosphorylation in a PKC- and ERK-Independent Manner" Int. J. Mol. Sci. 22, no. 4: 1777. https://doi.org/10.3390/ijms22041777

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