Jeffery L. Dunning, PhD
Arrestin-Derived Peptides as Novel Tools to Bias Cell Signaling and Combat L-DOPA Induced Dyskinesia
Summary
Arrestins ensure the termination of signaling by G protein-coupled receptors (GPCRs). Arrestins also simultaneously act as scaffolds for other proteins, initiating G protein-independent signaling within the cell. Dopaminergic signaling is mediated by GPCRs and plays a critical role in controlling multiple forms of behavior. Abnormalities of signaling by dopamine receptors have been strongly implicated in Parkinson’s disease (PD) and severe motor complications caused by dopamine replacement therapy, such as L-DOPA-induced dyskinesia (LID). Arrestins likely contribute to LID via their actions in targeting and colocalizing effector molecules. Mice lacking the genes for arrestin-3 demonstrate suppressed LID behaviors and the restoration of arrestin-3 in the basal ganglia restore these behaviors. Studies using arrestin-3 derived peptides in cell culture have identified that arrestin-3 may exert its effects through activation of the JNK pathway. It remains unknown, however, if arrestin-3-dependent JNK activation is the mechanism underlying LID. This project investigates the monofunctional elements of arrestin-3, their molecular targets, and tests the therapeutic potential “mini-scaffolds” in dampening cell signaling. The goal of this research is to explore how modulation of arrestin-3-dependent activity of the JNK pathway affects LID and will explore the feasibility of using the arrestin-3 derived peptides capable of preventing the arrestin3-dependent JNK activation as anti-LID therapy. The results of these experiments will shed light on the pharmacology of arrestin-3 action in regulating dopaminergic signaling in the brain, providing promising new molecular targets to meet unmet clinical needs.
