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.

Keywords: Dopamine receptors; Dopamine- and cAMP-regulated phosphoprotein of 32 kDa; Extracellular signal-regulated kinases 1 and 2; Gene transcription; Mammalian target of rapamycin; cAMP-dependent protein kinase.

Fig. 1

Schematic diagram illustrating the main mechanisms implicated in the sensitization of D1R associated with LID. In PD, the loss of dopamine input to the striatum increases the expression of the Gαolf protein and adenylyl cyclase type 5 (AC5). This change enhances the ability of D1R, which are expressed in the striatal projection neurons of the direct pathway (dSPN), to stimulate the synthesis of cAMP, a primary mediator of dopamine transmission. The increases in Gαolf protein and AC5 are paralleled by reduced expression of the G-protein-coupled receptor kinase 6 (GRK6), which decreases D1R phosphorylation, β-arrestin binding and receptor internalization. Dopamine depletion is also accompanied by increased expression of β-arrestin, which may counteract D1R sensitization. However, this effect is reversed by administration of l-DOPA. In contrast, overexpression of AC5 and, at least in part, Gαolf protein, as well as downregulation of GRK6, persists in dSPN even following administration of l-DOPA. Importantly, treatment with l-DOPA increases the levels of the postsynaptic density 95 (PSD-95) and dopamine D3 receptors (D3R). This further reinforces D1R-mediated transmission, leading to activation of the cAMP/PKA/DARPP-32, ERK and mTORC1 signaling cascades. The importance of these mechanisms is underscored by several studies, indicating that overexpression of GRK6 and β-arrestin, or downregulation of AC5 and PSD-95, decrease dyskinesia. In line with these findings, and further supporting the crucial role played by receptor sensitization in LID, this condition is also reduced by overexpression of the regulator of G-protein signaling 9-2 (RGS9-2), or by combining the administration of l-DOPA with D3R antagonists

Fig. 2

Diagram summarizing the central role played by abnormal ERK signaling in LID. Hyperactivation of ERK in response to stimulation of sensitized dopamine D1 receptors is emerging as a central point of convergence for several signaling pathways implicated in dyskinesia, including the cAMP/PKA/DARPP-32, the Ras-GRF1/Ras/MEK, the phospholipase C (PLC)/protein kinase C (PKC) and the Shp2/Src cascades. Pharmacological or genetic inhibition of various constituents of these intracellular pathways has been shown to reduce LID. Activation of ERK generates additional pathological responses, such as abnormal Rhes/mTORC1 signaling, and overexpression of ∆FosB (mediated by MSK1) and Narp. Several interventions counteracting these changes have been shown to reduce dyskinesia

Fig. 3

Summary of the main chromatin modifications associated with LID. During dyskinesia, ERK-mediated activation of mitogen- and stress-activated kinase 1 (MSK1) results in the phosphorylation of histone H3 at Ser10 and 28. Both modifications promote gene transcription. Enrichment of histone H3 phosphorylated at Ser10 has been reported to occur at the fosB promoter and may, therefore, participate in the accumulation of ∆FosB associated with LID. ∆FosB forms heterodimers with members of the jun family of transcription factors which bind to the activator protein-1 (AP-1) sites of late response genes to regulate their transcription. Phosphorylation of histone H3 at Ser28 counteracts the action of Polycomb group (PcG) proteins, which suppress gene transcription via methylation at Lys27. Enrichment of Ser28 phosphorylation, which leads to displacement of PcG, has been found at the promoters of several genes up-regulated in the striata of dyskinetic mice. LID is also accompanied by increased expression of DNA demethylases, such as Tet3 and Gadd45b. This regulation is paralleled by reduced methylation of CpG dense regions of DNA, which is indicative of increased transcriptional activity