Signal transduction in l-DOPA-induced dyskinesia: from receptor sensitization to abnormal gene expression

Abstract

A large number of signaling abnormalities have been implicated in the emergence and expression of l-DOPA-induced dyskinesia (LID). The primary cause for many of these changes is the development of sensitization at dopamine receptors located on striatal projection neurons (SPN). This initial priming, which is particularly evident at the level of dopamine D1 receptors (D1R), can be viewed as a homeostatic response to dopamine depletion and is further exacerbated by chronic administration of l-DOPA, through a variety of mechanisms affecting various components of the G-protein-coupled receptor machinery. Sensitization of dopamine receptors in combination with pulsatile administration of l-DOPA leads to intermittent and coordinated hyperactivation of signal transduction cascades, ultimately resulting in long-term modifications of gene expression and protein synthesis. A detailed mapping of these pathological changes and of their involvement in LID has been produced during the last decade. According to this emerging picture, activation of sensitized D1R results in the stimulation of cAMP-dependent protein kinase and of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa. This, in turn, activates the extracellular signal-regulated kinases 1 and 2 (ERK), leading to chromatin remodeling and aberrant gene transcription. Dysregulated ERK results also in the stimulation of the mammalian target of rapamycin complex 1, which promotes protein synthesis. Enhanced levels of multiple effector targets, including several transcription factors have been implicated in LID and associated changes in synaptic plasticity and morphology. This article provides an overview of the intracellular modifications occurring in SPN and associated with LID.

The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson’s Disease

“…Postsynaptic changes include a variety of structural and molecular adaptations in striatal projection neurons (medium spiny neurons, MSNs), following dopamine denervation and L-DOPA treatment [ 20 , 21 ]. These neuronal changes comprise “supersensitive” postsynaptic (D1) dopamine receptors in the direct pathway (striatonigral) MSNs (dMSNs) [ 22 , 23 , 24 ], which, in the presence of supraphysiological dopamine levels, produce aberrant second messenger signaling [ 9 , 24 , 25 ], resulting in facilitated neuronal activity (e.g., [ 26 ]) and enhanced transmitter release (e.g., [ 13 , 27 ]), as well as dysregulated gene expression [ 8 , 9 ] in these neurons. Studies have shown that L-DOPA treatment after dopamine lesions produces changes in the regulation of thousands of genes in MSNs (e.g., [ 9 , 28 , 29 , 30 ]), including those encoding various neuropeptides, receptors, and transcription factors, and several of these have been directly related to the occurrence or severity of L-DOPA-induced dyskinesia (e.g., [ 31 , 32 , 33 , 34 ]; [ 9 ], for review).…”

Dopamine D1 receptor signalling in dyskinetic Parkinsonian rats revealed by fiber photometry using FRET-based biosensors

“…A chronic regimen of L-DOPA/benserazide that induced dyskinesia also resulted in attenuation of this enhanced signalling, even though D1R-associated dyskinesia was significantly increased. The occurrence of D1R supersensitivity is well established in 6-OHDA lesioned rats [reviewed in 50,51 ], and a recent study using FRET-based biosensors has demonstrated hyperactivation of PKA and ERK1/2 by D1R agonists in striatal slices taken from 6-OHDA lesioned mice 52 . The present in vivo study extends these ex vivo findings, by showing that acute D1R-induced PKA and ERK1/2 activation is suppressed by repeated L-DOPA treatment, suggesting that while D1R signalling may be desensitized by chronic L-DOPA treatment, the D1R-driven dyskinesia nevertheless increases.…”

In silico drug screening by using genome-wide association study data repurposed dabrafenib, an anti-melanoma drug, for Parkinson’s disease

“…Several studies have suggested that L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia is associated with the activation of ERK ( 61 ). Dabrafenib also activates ERK in cells with wild-type BRAF and thus may potentially exacerbate dyskinesia.…”