Decrease of K_ATP channel expression through D3 receptor-mediated GSK3β signaling alleviates levodopa-induced...

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.

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).

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.

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.