Decrease of KATP channel expression through D3 receptor-mediated GSK3β signaling alleviates levodopa-induced dyskinesia (LID) in Parkinson's disease mouse model

Yi-Ying Kuo; Sih-Yu Pen; Chia-Hui Cheng; Wan-Chen Ho; Ching-Yi Chen; Wen-Chung Wu; Ho-Hsuan Chou; Jung-Yao Chen; Ching-Han Lin; Jen-Feng Lin; Shi-Bing Yang; Pei-Chun Chen

doi:10.1016/j.lfs.2024.123255

Decrease of K_ATP channel expression through D3 receptor-mediated GSK3β signaling alleviates levodopa-induced dyskinesia (LID) in Parkinson's disease mouse model

Life Sci. 2024 Nov 16:359:123255. doi: 10.1016/j.lfs.2024.123255. Online ahead of print.

Authors

Yi-Ying Kuo¹, Sih-Yu Pen², Chia-Hui Cheng², Wan-Chen Ho², Ching-Yi Chen³, Wen-Chung Wu⁴, Ho-Hsuan Chou⁵, Jung-Yao Chen⁶, Ching-Han Lin⁷, Jen-Feng Lin⁸, Shi-Bing Yang⁹, Pei-Chun Chen¹⁰

Affiliations

¹ Department of Physiology, College of Medicine, National Cheng Kung Univesity, Tainan 70101, Taiwan; Institue of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
² Department of Physiology, College of Medicine, National Cheng Kung Univesity, Tainan 70101, Taiwan.
³ Department of Chemical Engineering, National Chung Cheng University, Chiayi 62102, Taiwan.
⁴ Department of Chemical Engineering, National Cheng Kung University, Tainan 70101, Taiwan.
⁵ Department of Chemistry, National Cheng Kung University, Tainan 70101, Taiwan.
⁶ Department of Photonics, National Cheng Kung University, Tainan 70101, Taiwan.
⁷ Division of Endocrinology and Metabolism, Department of Internal Medicine, National Cheng Kung University Hospital, Taiwan.
⁸ Department of Emergency, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Taiwan.
⁹ Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
¹⁰ Department of Physiology, College of Medicine, National Cheng Kung Univesity, Tainan 70101, Taiwan; Institue of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan. Electronic address: pcchen@mail.ncku.edu.tw.

PMID: 39557392
DOI: 10.1016/j.lfs.2024.123255

Abstract

Aims: The standard Parkinson's disease (PD) treatment is L-3,4-dihydroxyphenylalanine (L-DOPA); however, its long-term use may cause L-DOPA-induced dyskinesia (LID). Aberrant activation of medium spiny neurons (MSNs) contributes to LID, and MSN excitability is regulated by dopamine D3 receptor (D3R) and ATP-sensitive potassium (K_ATP) channel activity. Nevertheless, it remains unclear if D3R and K_ATP channels may be linked in the context of LID.

Methods: Wild-type and tyrosine hydroxylase (TH)-specific Kir6.2 knockout mice were injected with 6-hydroxydopamine (6-OHDA) to generate a PD mouse model, then chronically treated with L-DOPA to induce LID. Analyses included immunohistochemical staining, biochemical endpoints, and behavior tests. The mechanisms by which D3R/K_ATP channels regulate LID in the PD/LID mouse model were probed by treatment with a D3R antagonist, K_ATP channel opener and glycogen synthase kinase 3β (GSK3β) inhibitor, followed by evaluation of abnormal involuntary movements (AIMs).

Key findings: The D3R antagonist FAUC365 alleviated LID, reducing AIMs and protecting against degeneration of the nigrostriatal pathway, which occurred through a direct interaction between D3Rs and K_ATP channels. In line with this mechanism, activation of D3R/GSK3β signaling increased K_ATP channel expression in the striatum of PD/LID mice. Additionally, the K_ATP channel opener Diz slowed LID progression and preserved nigrostriatal projections. Consistently, mice with TH-specific knockout of Kir6.2 exhibited reduced PD-like symptoms and less severe LID.

Significance: D3Rs act through GSK3β signaling to regulate expression of K_ATP channels, which may subsequently modulate LID. Inhibition of K_ATP channels in TH-positive cells is sufficient to reduce AIMs in a mouse model of PD/LID.

Keywords: ATP-sensitive potassium channel; Diazoxide; Dopamine; Levodopa-induced dyskinesia; Parkinson's disease.