Die Aktivierung von SK-Kanälen in einem Parkinson-Zellmodell

Die Aktivierung der kalziumabhängigen Kaliumkanäle mit kleiner Leitfähigkeit (KCNN/SK/KCa2) ist ein vielversprechender therapeutischer Ansatz für die Behandlung von neurologischen Erkrankungen wie Schlaganfall, amyotrophe Lateralsklerose (ALS), Ataxie und Schizophrenie. In dieser Studie wurde das th...

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Bibliographic Details
Main Author: Andrade, Anderson Cleyton Ferreira de
Contributors: Höglinger, Günter (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2014
Online Access:PDF Full Text
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Activation of Calcium-dependent potassium channels with small conductance (KCNN/SK/KCa2) plays an important role in neurological diseases such as stroke, amyotrophic lateral sclerosis, ataxia or schizophrenia. This study addresses the therapeutic potential of SK channel activation in a rotenone- based Parkinson in vitro model. Dopaminergic neurons from an immortalized human cell line differentiated over 6 days (LUHMES cells) was used as cell model. The concentration-dependent treatment with the complex I-inhibitor rotenone (0.1-2.0 μM) destroyed the dendritic network of differentiated dopaminergic neurons and caused cell death. Quantitative RT-PCR and Western blot analysis demonstrated the differentiated dopaminergic neurons express sparsely SK2 channels and largely SK1 and SK3 channels. Protein analysis of subcellular fractions showed localization of SK2 channel subtypes in mitochondria. The positive SK channel modulator NS309 reduced the mitochondrial membrane potential whereas dendritic network, viability and ATP levels of cells sustained after rotenone treatment. Taken together, the findings showed activation of SK channels promoted protective effects in human dopaminergic neurons, likely via activation of mitochondrial membrane potential by SK channels. Activation of SK channels, hence, is a very promising therapeutic approach for treatment of neurodegenerative diseases such as Parkinson disease in that dopaminergic cell loss is associated with disease progress.