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Roles of Glutamate Receptors in Parkinson's Disease

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Roles of Glutamate Receptors in Parkinson's Disease International Journal of Molecular Sciences Review Roles of Glutamate Receptors in Parkinson’s Disease 1,2,3, 2,3, 2,3 2,3 2,3 Zhu Zhang y, Shiqing Zhang y, Pengfei Fu , Zhang Zhang , Kaili Lin , Joshua Ka-Shun Ko 1,* and Ken Kin-Lam Yung 2,3,* 1 Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR999077, China 2 Department of Biology,Hong Kong Baptist University,Kowloon Tong, Kowloon, Hong Kong SAR 999077, China 3 Golden Meditech Center for NeuroRegeneration Sciences (GMCNS), Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong SAR999077, China * Correspondence: [email protected] (J.K.-S.K.); [email protected] (K.K.-L.Y.); Tel.: +852-3411-2907 (J.K.-S.K.); +852-3411-7060 (K.K.-L.Y.); Fax: +852-3411-2461 (J.K.-S.K.); +852-3411-5995 (K.K.-L.Y.) These authors contributed equally to this work. y Received: 8 August 2019; Accepted: 27 August 2019; Published: 6 September 2019 Abstract: Parkinson’s disease is a progressive neurodegenerative disorder resulting from the degeneration of pigmented dopaminergic neurons in the substantia nigra pars compacta. It induces a series of functional modifications in the circuitry of the basal ganglia nuclei and leads to severe motor disturbances. The amino acid glutamate, as an excitatory neurotransmitter, plays a key role in the disruption of normal basal ganglia function regulated through the interaction with its receptor proteins. It has been proven that glutamate receptors participate in the modulation of neuronal excitability, transmitter release, and long-term synaptic plasticity, in addition to being related to the altered neurotransmission in Parkinson’s disease. Therefore, they are considered new targets for improving the therapeutic strategies used to treat Parkinson’s disease. In this review, we discuss the biological characteristics of these receptors and demonstrate the receptor-mediated neuroprotection in Parkinson’s disease. Pharmacological manipulation of these receptors during anti-Parkinsonian processes in both experimental studies and clinical trials are also summarized. Keywords: Parkinson’s disease; glutamate receptors; NMDA receptor; mGluR4; mGluR5 1. Introduction Parkinson’s disease (PD) is a debilitating neurodegenerative disorder which is second to Alzheimer’s disease as the most common age-related disease. The clinical symptoms of PD include motor disturbances (such as resting tremor, bradykinesia), rapid eye movement behavior disorder, as well as autonomic and cognitive impairment [1]. The pathology underlying PD comprises the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the accumulation of intracytoplasmic inclusions, which are known as Lewy bodies in these neurons [2]. Therefore, dopamimetic drugs, including the dopamine precursor levodopa (l-3,4-dihydroxyphenylalanine, l-DOPA), and dopamine receptor agonists are currently considered as the only standard therapy for treating Parkinsonian symptoms [3]. Although these treatments ameliorate the motor signs of PD for several years in most patients, prolonged therapy frequently leads to the development of motor complications, known as L-DOPA-induced-dyskinesia (LID), such as choreic or larger amplitude choreo-athetotic movements, dystonia, and ballism [4]. It is known that different neurotransmitter systems in the human brain and central nervous system (CNS) are involved in the pathophysiology of PD and LID. Among these, glutamate takes up 40% of all synapses and plays an important role in the mediation of basal ganglia circuitry in continuous feedback, leading to the dopaminergic denervation of the striatum [5]. Moreover, an increasing body of evidence has Int. J. Mol. Sci. 2019, 20, 4391; doi:10.3390/ijms20184391 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 2 of 17 Int. J. Mol. Sci. 2019, 20, 4391 2 of 17 demonstrated the contribution of glutamatergic transmission to the processes of PD and LID [4]. It was also determined that the concentration of serum glutamate in PD patients is higher than that in healthydemonstrated subjects the [6]. contribution Therefore, of glutamatergicit has been su transmissionggested that to pharmacological the processes of PD therapies and LID [with4]. It wasthe potentialalso determined to restore that normal the concentration glutamatergic of serum function glutamates show in promise PD patients as therapeutic is higher than interventions that in healthy by reversingsubjects [6the]. Therefore,severe motor it has complications been suggested that that derive pharmacological from the current therapies dopamine with the replacement potential to strategies.restore normal glutamatergic functions show promise as therapeutic interventions by reversing the severeGlutamate motor complications plays a critical that role derive in brain from function the current through dopamine multiple replacement receptor strategies.proteins which are primarilyGlutamate located plays on pre- a critical and post-synaptic role in brain neurons function in throughvirtually multiple all areas receptorof the CNS. proteins Figure which 1 shows are thatprimarily glutamate located receptors on pre- were and originally post-synaptic classified neurons into two in virtuallymajor classes all areas of ionotropic of the CNS. (iGluRs) Figure and1 metabotropicshows that glutamatereceptors (mGluRs), receptors wereaccording originally to pharmacological classified into means. two major The iGluRs classes are of multimeric ionotropic ion(iGluRs) channels and and metabotropic are responsible receptors for fast (mGluRs), excitatory according transmission to pharmacological in the mammalian means. CNS. The Through iGluRs bindingare multimeric the presynaptically ion channels andreleased are responsible glutamate, foriGluRs fast excitatorytransduce transmission signals into inthe the excitation mammalian of postsynapticCNS. Through neurons binding on a the millisecond presynaptically timescale. released This process glutamate, generates iGluRs a synaptic transduce current signals crucial into theto brainexcitation function of postsynapticand regulates neurons learning onand a memory. millisecond iGluRs timescale. can be further This process classified generates into N-methyl- a synapticD- aspartatecurrent crucial (NMDA) to brain receptors, function andα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic regulates learning and memory. iGluRs can be furtheracid classified(AMPA) receptors,into N-methyl- and kainated-aspartate receptors. (NMDA) As members receptors, ofα the-amino-3-hydroxy-5-methyl-4-isoxazolepropionic G-protein receptors superfamily, the mGluRs mediateacid (AMPA) slow glutamate receptors, responses, and kainate which receptors. contributes As members to long-lasting of the G-protein changes in receptors synaptic superfamily,activity [7]. Thethe mGluRsmGluRs mediatefamily can slow be glutamate further divided responses, into which eight contributesreceptor subtypes. to long-lasting Based changeson their in sequence synaptic homology,activity [7]. signal The mGluRs transduction family canmechanisms, be further dividedand pharmacological into eight receptor profile, subtypes. these Basedsubtypes on theirare classifiedsequence into homology, three groups. signal transductionGroup I receptors mechanisms, include andmGluR1 pharmacological and mGluR5, profile, which these are linked subtypes to phospholipaseare classified into C-mediated three groups. polyphosphoinositide Group I receptors includehydrolysis, mGluR1 while and group mGluR5, II includes which mGluR2 are linked and to mGluR3,phospholipase which C-mediatedin recombinant polyphosphoinositide systems are negatively hydrolysis, coupled while to groupadenylate II includes cyclase. mGluR2 Group andIII consistsmGluR3, of which mGluR4, in recombinant −6, −7, and systems−8, which are are negatively also negatively coupled coupled to adenylate to adenylate cyclase. cyclase Group IIIor consistslinked toof ion mGluR4, channels6, [8].7, andIn the8, pathophysiology which are also negatively of PD, there coupled are regulatory to adenylate alterations cyclase or of linked glutamate to ion − − − receptorschannels in [8 ].specific In the pathophysiologyloci in the basal ganglia. of PD, thereIn addition, are regulatory glutamate alterations receptors of are glutamate also changed receptors in the in processspecific of loci LID, in thesuch basal as the ganglia. increased In addition, specific glutamatebinding of receptorsNMDA receptors are also changed and decreased in the processmGlu2/3 of receptorsLID, such after as the levodopa increased treatment specific bindingin 1-methyl-4-p of NMDAhenyl-1,2,3,6-tetrahydropyridine receptors and decreased mGlu2 (MPTP)-lesioned/3 receptors after monkeyslevodopa [9]. treatment in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys [9]. Figure 1. Classification of glutamate receptors. Figure 1. Classification of glutamate receptors. Therefore, a comprehensive understanding of glutamate receptors, concerning both the pathophysiologyTherefore, a andcomprehensive the treatment understanding targets of PD, of may glutamate contribute receptors, to the developmentconcerning both of novel the pathophysiologytherapeutic approaches and the to PD.treatment In this review,targets weof PD, discuss may the contribute distribution to ofthe these development different subtypes of novel of therapeuticglutamate receptorsapproaches and to their PD. neuroprotectiveIn this review, we properties, discuss the as welldistribution
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