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Prolyl Oligopeptidase Regulates Dopamine Transporter Oligomerization and Phosphorylation in a PKC- and ERK-Independent Manner.
Julku, Ulrika H; Jäntti, Maria; Svarcbahs, Reinis; Myöhänen, Timo T.
Afiliación
  • Julku UH; Division of Pharmacology and Pharmacotherapy/Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E (P.O. Box 56), FI-00014 Helsinki, Finland.
  • Jäntti M; Division of Pharmacology and Pharmacotherapy/Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E (P.O. Box 56), FI-00014 Helsinki, Finland.
  • Svarcbahs R; Division of Pharmacology and Pharmacotherapy/Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E (P.O. Box 56), FI-00014 Helsinki, Finland.
  • Myöhänen TT; Division of Pharmacology and Pharmacotherapy/Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E (P.O. Box 56), FI-00014 Helsinki, Finland.
Int J Mol Sci ; 22(4)2021 Feb 10.
Article en En | MEDLINE | ID: mdl-33579026
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína Quinasa C / Quinasas MAP Reguladas por Señal Extracelular / Proteínas de Transporte de Dopamina a través de la Membrana Plasmática / Prolil Oligopeptidasas Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2021 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína Quinasa C / Quinasas MAP Reguladas por Señal Extracelular / Proteínas de Transporte de Dopamina a través de la Membrana Plasmática / Prolil Oligopeptidasas Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2021 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: Suiza