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Dopamine D2 receptor and ?-arrestin 2 mediate Amyloid-? elevation induced by anti-parkinson's disease drugs, levodopa and piribedil, in neuronal cells.

ABSTRACT: Although levodopa is the first-line medication for the treatment of Parkinson's disease (PD) showing unsurpassable efficiency, its chronic use causes dyskinesia. Accordingly, dopamine agonists are increasingly employed as monotherapy or in combination with levodopa to reduce the risk of motor complications. It is well recognized that patients with PD often exhibit cognitive deficits. However, clinical and animal studies assessing the effects of dopaminergic medications on cognition are controversial. Amyloid-? (A?) is one of the major hallmarks of Alzheimer's disease (AD), leading to progressive memory loss and cognitive deficit. Interestingly, the abnormal accumulation of A? is also detected in PD patients with cognitive deficits. Evidence indicated that levodopa induced a mild increase of A? plaque number and size in the brain of AD mouse. However, the underlying mechanism is unclear. Here we present that both levodopa and piribedil enhance the generation of A? and the activity of ?-secretase in human neuronal cells and primary neurons isolated from AD mouse. This effect was reduced by either the antagonism or the knockdown of dopamine D2 receptor (D2R). We further showed that in the cells expressing ?-arrestin 2-biased D2R mutant, piribedil promoted cellular A? production to the extent comparable to the wild-type D2R whereas this activity was absent in those with G protein-biased D2R mutant. Moreover, the knockdown of ?-arrestin 2 attenuated the increases of A? generation and ?-secretase activity mediated by levodopa or piribedil. Thus, our study suggests that targeting D2R-mediated ?-arrestin function may have potential risk in the modulation of A? pathology.

SUBMITTER: Lu J

PROVIDER: S-EPMC5333886 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Dopamine D2 receptor and β-arrestin 2 mediate Amyloid-β elevation induced by anti-parkinson's disease drugs, levodopa and piribedil, in neuronal cells.

Lu Jing J Li Xiaohang X Wang Qinying Q Pei Gang G

PloS one 20170302 3

Although levodopa is the first-line medication for the treatment of Parkinson's disease (PD) showing unsurpassable efficiency, its chronic use causes dyskinesia. Accordingly, dopamine agonists are increasingly employed as monotherapy or in combination with levodopa to reduce the risk of motor complications. It is well recognized that patients with PD often exhibit cognitive deficits. However, clinical and animal studies assessing the effects of dopaminergic medications on cognition are controver ...[more]

PMID: 28253352

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Project description:BackgroundNo clinical trials have been specifically designed to compare medical treatments after surgery in Parkinson's disease (PD).ObjectiveStudy's objective was to compare the efficacy and safety of levodopa versus dopamine agonist monotherapy after deep brain stimulation (DBS) in PD.MethodsThirty-five surgical candidates were randomly assigned to receive postoperative monotherapy with either levodopa or dopamine agonist in a randomized, single-blind study. All patients were reevaluated in short- (3 months), mid- (6 months), and long-term (2.5 years) follow-up after surgery. The primary outcome measure was the change in the Non-Motor Symptoms Scale (NMSS) 3 months after surgery. Secondary outcome measures were the percentage of patients maintaining monotherapy, change in motor symptoms, and specific non-motor symptoms (NMS). Analysis was performed primarily in the intention-to-treat population.ResultsRandomization did not significantly affect the primary outcome (difference in NMSS between treatment groups was 4.88 [95% confidence interval: -11.78-21.53, P = 0.566]). In short- and mid-term follow-up, monotherapy was safe and feasible in more than half of patients (60% in short- and 51.5% in mid-term follow-up), but it was more often possible for patients on levodopa. The ability to maintain dopamine agonist monotherapy was related to optimal contact location. In the long term, levodopa monotherapy was feasible only in a minority of patients (34.2%), whereas dopamine agonist monotherapy was not tolerated due to worsening of motor conditions or occurrence of impulse control disorders.ConclusionsThis trial provides evidence for simplifying pharmacological treatment after functional neurosurgery for PD. The reduction in dopamine receptor agonists should be attempted while monitoring for occurrence of NMSs, such as apathy and sleep disturbances. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Project description:PurposeThe G-protein coupled receptor (GPCR) Dopamine Receptor D4 (DRD4) plays an essential role in cAMP regulation and gap junctional coupling in the photoreceptors, where DRD4 expression is under circadian control. Previous in vitro transfection studies of human DRD4 desensitization have reported that DRD4 is not internalized upon dopamine stimulation when beta-arrestin is co-transfected with DRD4. We hypothesized that the visual arrestins, ARR1 and ARR4, play a modulatory role in DRD4 desensitization in the photoreceptors.MethodsTo test this hypothesis, immunohistochemistry analysis of mouse retinas was used to determine the cellular localization of beta-arrestins and DRD4 in photoreceptors. In vitro studies were performed in HEK293T cells transiently transfected with human DRD4 and arrestins. First, co-immunoprecipitation experiments were executed to test protein-protein interactions and to investigate the effect of dopamine stimulation. Second, immunohistochemistry analysis was implemented to study DRD4 internalization and translocation of ARR4.ResultsImmunohistochemistry studies of mouse retinas confirmed the expression of beta-arrestin 2, ARR1 and ARR4, as well as DRD4 in mouse cone photoreceptor inner segments. Co-immunoprecipitation experiments revealed a dopamine-dependent protein-protein interaction between human DRD4 and ARR4. In vitro internalization experiments showed that no detectable internalization of DRD4 was observed with any single arrestin co-transfected. However, a dopamine-dependent internalization of DRD4 was observed with three out of six sets of two arrestins co-transfected with DRD4. Each of these pairs of arrestins contained one visual arrestin and one beta-arrestin, and no internalization was observed with either two visual arrestins or two beta-arrestins. Additional time-course experiments revealed that in vitro, ARR4 translocates to co-localize with DRD4 at the plasma membrane in response to 30min of dopamine stimulation.ConclusionsThe results have functional implications and we hypothesize that the desensitization and internalization of DRD4 in photoreceptors are synergistically mediated by both visual and beta-arrestins. These results are additionally unique because they demonstrate for the first time that at least one G-protein coupled receptor, DRD4, requires two arrestins for desensitization and internalization, and opens up the possibility that other G-protein coupled receptors may require more than one arrestin for desensitization and/or internalization.

Dataset Information

Dopamine D2 receptor and ?-arrestin 2 mediate Amyloid-? elevation induced by anti-parkinson's disease drugs, levodopa and piribedil, in neuronal cells.

Publications

Dopamine D2 receptor and β-arrestin 2 mediate Amyloid-β elevation induced by anti-parkinson's disease drugs, levodopa and piribedil, in neuronal cells.

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