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      A2A-D2 Heteromers on Striatal Astrocytes: Biochemical and Biophysical Evidence

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          Abstract

          Our previous findings indicate that A2A and D2 receptors are co-expressed on adult rat striatal astrocytes and on the astrocyte processes, and that A2A-D2 receptor–receptor interaction can control the release of glutamate from the processes. Functional evidence suggests that the receptor–receptor interaction was based on heteromerization of native A2A and D2 receptors at the plasma membrane of striatal astrocyte processes. We here provide biochemical and biophysical evidence confirming that receptor–receptor interaction between A2A and D2 receptors at the astrocyte plasma membrane is based on A2A-D2 heteromerization. To our knowledge, this is the first direct demonstration of the ability of native A2A and D2 receptors to heteromerize on glial cells. As striatal astrocytes are recognized to be involved in Parkinson’s pathophysiology, the findings that adenosine A2A and dopamine D2 receptors can form A2A-D2 heteromers on the astrocytes in the striatum (and that these heteromers can play roles in the control of the striatal glutamatergic transmission) may shed light on the molecular mechanisms involved in the pathogenesis of the disease.

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          Most cited references 55

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          Current and experimental treatments of Parkinson disease: A guide for neuroscientists.

          Over a period of more than 50 years, the symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been optimized using pharmacotherapy, deep brain stimulation, and physiotherapy. The arsenal of pharmacotherapies includes L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine. In the later course of the disease, motor complications occur, at which stage different oral formulations of L-Dopa or dopamine agonists with long half-life, a transdermal application or parenteral pumps for continuous drug supply can be subscribed. Alternatively, the patient is offered deep brain stimulation of the subthalamic nucleus (STN) or the internal part of the globus pallidus (GPi). For a more efficacious treatment of motor complications, new formulations of L-Dopa, dopamine agonists, and amantadine as well as new MAO-B and COMT inhibitors are currently tested in clinical trials, and some of them already yielding positive results in phase 3 trials. In addition, non-dopaminergic agents have been tested in the early clinical phase for the treatment of motor fluctuations and dyskinesia, including adenosine A2A antagonists (istradefylline, preladenant, and tozadenant) and modulators of the metabolic glutamate receptor 5 (mGluR5 - mavoglurant) and serotonin (eltoprazine) receptors. Recent clinical trials testing coenzyme Q10, the dopamine agonist pramipexole, creatine monohydrate, pioglitazone, or AAV-mediated gene therapy aimed at increasing expression of neurturin, did not prove efficacious. Treatment with nicotine, caffeine, inosine (a precursor of urate), and isradipine (a dihydropyridine calcium channel blocker), as well as active and passive immunization against α-synuclein and inhibitors or modulators of α-synuclein-aggregation are currently studied in clinical trials. However, to date, no disease-modifying treatment is available. We here review the current status of treatment options for motor and non-motor symptoms, and discuss current investigative strategies for disease modification. This review provides basic insights, mainly addressing basic scientists and non-specialists. It stresses the need to intensify therapeutic PD research and points out reasons why the translation of basic research to disease-modifying therapies has been unsuccessful so far. The symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine), deep brain stimulation, and physiotherapy. For a more efficacious treatment of motor complications, new formulations of L-Dopa, dopamine agonists, and amantadine as well as new MAO-B and COMT inhibitors are currently tested in clinical trials. Non-dopaminergic agents have been tested in the early clinical phase for the treatment of motor fluctuations and dyskinesia. Recent clinical trials testing coenzyme Q10, the dopamine agonist pramipexole, creatine monohydrate, pioglitazone, or AAV-mediated gene therapy aimed at increasing expression of neurturin, did not prove efficacious. Treatment with nicotine, caffeine, and isradipine - a dihydropyridine calcium channel blocker - as well as active and passive immunization against α-synuclein and inhibitors of α-synuclein-aggregation are currently studied in clinical trials. However, to date, no disease-modifying treatment is available for PD. We here review the current status of treatment options and investigative strategies for both motor and non-motor symptoms. This review stresses the need to intensify therapeutic PD research and points out reasons why the translation of basic research to disease-modifying therapies has been unsuccessful so far. This article is part of a special issue on Parkinson disease.
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            G Protein-Coupled Receptor Heteromers.

            G protein-coupled receptors (GPCRs) compose one of the largest families of membrane proteins involved in intracellular signaling. They are involved in numerous physiological and pathological processes and are prime candidates for drug development. Over the past decade, an increasing number of studies have reported heteromerization between GPCRs. Many investigations in heterologous systems have provided important indications of potential novel pharmacology; however, the physiological relevance of these findings has yet to be established with endogenous receptors in native tissues. In this review, we focus on family A GPCRs and describe the techniques and criteria to assess their heteromerization. We conclude that advances in approaches to study receptor complex functionality in heterologous systems, coupled with techniques that enable specific examination of native receptor heteromers in vivo, are likely to establish GPCR heteromers as novel therapeutic targets.
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              Detection of antigen interactions ex vivo by proximity ligation assay: endogenous dopamine D2-adenosine A2A receptor complexes in the striatum.

              The existence of G protein-coupled receptor (GPCR) dimers and/or oligomers has been demonstrated in heterologous systems using a variety of biochemical and biophysical assays. While these interactions are the subject of intense research because of their potential role in modulating signaling and altering pharmacology, evidence for the existence of receptor interactions in vivo is still elusive because of a lack of appropriate methods to detect them. Here, we adapted and optimized a proximity ligation assay (PLA) for the detection in brain slices of molecular proximity of two antigens located on either the same or two different GPCRs. Using this approach, we were able to confirm the existence of dopamine D2 and adenosine A2A receptor complexes in the striatum of mice ex vivo.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                17 May 2019
                May 2019
                : 20
                : 10
                Affiliations
                [1 ]Department of Pharmacy, Section of Pharmacology and Toxicology, University of Genova, Viale Cembrano 4, 16148 Genova, Italy; pelassa@ 123456difar.unige.it (S.P.); a.venturini@ 123456tigem.it (A.V.); frumento@ 123456difar.unige.it (G.F.); maura@ 123456difar.unige.it (G.M.); marcoli@ 123456pharmatox.unige.it (M.M.)
                [2 ]Department of Neuroscience, University of Padova, Via Gabelli 63, 35122 Padova, Italy; diego.guidolin@ 123456unipd.it
                [3 ]Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV, 1, 16132 Genova, Italy; monica.averna@ 123456unige.it
                [4 ]Division of Experimental Oncology, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy; Letizia.campanini@ 123456gmail.com (L.C.); bernardi.rosa@ 123456hsr.it (R.B.)
                [5 ]Department of Biomedical and NeuroMotor Sciences (DIBINEM) Alma Mater Studiorum-University of Bologna, Via Altura 3, 40139 Bologna, Italy; pietro.cortelli@ 123456unibo.it (P.C.); giovanna.calandra@ 123456unibo.it (G.C.B.)
                [6 ]IRCCS Istituto delle Scienze Neurologiche di Bologna, Via Altura 3, 40139 Bologna, Italy
                [7 ]Department of Diagnostic, Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy; luigi.agnati@ 123456gmail.com
                [8 ]Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 171 65 Stockholm, Sweden
                [9 ]Centre of Excellence for Biomedical Research CEBR, University of Genova, Viale Benedetto XV, 5, 16132 Genova, Italy
                Author notes
                [* ]Correspondence: cervetto@ 123456difar.unige.it ; Tel.: +39-010-3352038
                [†]

                Present address: Telethon Institute of Genetics and Medicine (TIGEM) Via Campi Flegrei 34, 80078, Pozzuoli (NA), Italy.

                [‡]

                Present address: Department of surgical, medical, dental and morphological sciences-University of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy.

                Article
                ijms-20-02457
                10.3390/ijms20102457
                6566402
                31109007
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                Categories
                Communication

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