Targeting β-arrestin2 in the treatment ofl-DOPA–induced dyskinesia in Parkinson’s disease

Abstract

Parkinson's disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine (DA) precursor L-3,4-dihydroxyphenylalanine (L-DOPA), but its prolonged use causes dyskinesias referred to as L-DOPA-induced dyskinesias (LIDs). Recent studies in animal models of PD have suggested that dyskinesias are associated with the overactivation of G proteinmediated signaling through DA receptors. β-Arrestins desensitize G protein signaling at DA receptors (D1R and D2R) in addition to activating their own G protein-independent signaling events, which have been shown to mediate locomotion. Therefore, targeting β-arrestins in PD L-DOPA therapy might prove to be a desirable approach. Here we show in a bilateral DA-depletion mouse model of Parkinson's symptoms that genetic deletion of β-arrestin2 significantly limits the beneficial locomotor effects while markedly enhancing the dyskinesia-like effects of acute or chronic L-DOPA treatment. Viral rescue or overexpression of β-arrestin2 in knockout or control mice either reverses or protects against LIDs and its key biochemical markers. In other more conventional animal models of DA neuron loss and PD, such as 6-hydroxydopamine-treated mice or rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated nonhuman primates, β-arrestin2 overexpression significantly reduced dyskinesias while maintaining the therapeutic effect of L-DOPA. Considerable efforts are being spent in the pharmaceutical industry to identify therapeutic approaches to block LIDs in patients with PD. Our results point to a potential therapeutic approach, whereby development of either a genetic or pharmacological intervention to enhance β-arrestin2-or limit G protein-dependent D1/D2R signaling could represent a more mechanistically informed strategy.is a major catecholamine neurotransmitter that is released by midbrain DA neurons. DA activates G protein-coupled receptors (GPCRs), which belong to the dopamine D1 (D1R and D5R) or D2 (D2R, D3R, and D4R) class of DA receptors that are known to signal via G protein-dependent mechanisms (1, 2). However, recent studies have shown that in addition to G protein-mediated signaling, many GPCRs, including DA receptors, signal through beta-arrestin 1 and 2 (βarr1 and βarr2)-dependent mechanisms (3, 4). The two isoforms of β-arrestin, β-arrestin1 (βarr1) and β-arrestin2 (βarr2) are widely coexpressed in the brain (5, 6). β-Arrestins were originally appreciated for their ability to desensitize (i.e., turn off) GPCR signaling in a GPCR kinase (GRK)-dependent manner (7,8). Binding of β-arrestin to the GPCR sterically hinders G protein binding and in most instances initiates receptor endocytosis via interactions with adaptor protein complex-2 (AP-2) and clathrin (9-11). It is now appreciated that β-arrestins regulate physiology and behaviors independently of G protein signaling through their ability to scaffold multiple intracellular signaling molecules such as kinases and phosphatases (3,4,12,13). Studies from our laboratory have shown that through ...

Ghrelin receptor antagonism of hyperlocomotion in cocaine‐sensitized mice requires βarrestin‐2

“…DAT‐Cre mice (SG62 GENSAT and Jackson Laboratory #006660) were bred to floxed βarrestin‐2 mice (Urs et al, ) for homozygosity at the floxed allele and were used for behavioral experiments. To check for Cre activity in dopamine neurons, the SG62 GENSAT DAT‐Cre line was also bred to a Cre reporter mouse line consisting of a Cre‐dependent GFP‐tagged ribosomal L10a subunit.…”

Viral‐mediated oligodendroglial alpha‐synuclein expression models multiple system atrophy

“…Under sterile conditions, rats were anesthetized with isofluorane and secured in a stereotaxic frame (David Kopf Instruments, Tujunga, CA). All rats were injected bilaterally in the striatum (anteroposterior [AP]: + 0.68; mediolateral [ML]: ± 3.5; dorsoventral [DV]: –4.7; in millimeters; from bregma and pial surface) with a total of 10 µL of viral vector containing GFP‐degron (2.53 × 10 13 vg/mL; n = 13) or hα‐syn (2.33 × 10 13 vg/mL; n = 14) as previously described . Briefly, a Hamilton syringe with a 33‐Ga needle was used for AAV delivery (5 µL per site) at a rate of 0.5 µL per minute using a Kopf microinjector.…”

The dopamine D2 receptor can directly recruit and activate GRK2 without G protein activation

“…Functionally selective drugs are predicted to have increased specificity of action by only engaging the therapeutically relevant pathway, while avoiding activation of potential side-effect inducing pathways (14)(15)(16). For the dopamine D2 receptor (D2R), selective targeting of the D2R/barr signaling pathway may improve drugs used to treat schizophrenia, Parkinson's disease, or other disorders (15,17,18).…”