A Mini-review of the Role of Vesicular Glutamate Transporters in Parkinson's Disease

Overview

Journal Front Mol Neurosci

Specialty Molecular Biology

Date 2023 May 30

PMID 37251642

Authors

Cheng Zhao

Chunyu Wang

Hainan Zhang

Weiqian Yan

Affiliations

Soon will be listed here.

Abstract

Parkinson's disease (PD) is a common neurodegenerative disease implicated in multiple interacting neurotransmitter pathways. Glutamate is the central excitatory neurotransmitter in the brain and plays critical influence in the control of neuronal activity. Impaired Glutamate homeostasis has been shown to be closely associated with PD. Glutamate is synthesized in the cytoplasm and stored in synaptic vesicles by vesicular glutamate transporters (VGLUTs). Following its exocytotic release, Glutamate activates Glutamate receptors (GluRs) and mediates excitatory neurotransmission. While Glutamate is quickly removed by excitatory amino acid transporters (EAATs) to maintain its relatively low extracellular concentration and prevent excitotoxicity. The involvement of GluRs and EAATs in the pathophysiology of PD has been widely studied, but little is known about the role of VGLUTs in the PD. In this review, we highlight the role of VGLUTs in neurotransmitter and synaptic communication, as well as the massive alterations in Glutamate transmission and VGLUTs levels in PD. Among them, adaptive changes in the expression level and function of VGLUTs may exert a crucial role in excitatory damage in PD, and VGLUTs are considered as novel potential therapeutic targets for PD.

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References

El Mestikawy S, Wallen-Mackenzie A, Fortin G, Descarries L, Trudeau L . From glutamate co-release to vesicular synergy: vesicular glutamate transporters. Nat Rev Neurosci. 2011; 12(4):204-16. DOI: 10.1038/nrn2969. View

Birgner C, Nordenankar K, Lundblad M, Mendez J, Smith C, Le Greves M . VGLUT2 in dopamine neurons is required for psychostimulant-induced behavioral activation. Proc Natl Acad Sci U S A. 2009; 107(1):389-94. PMC: 2806710. DOI: 10.1073/pnas.0910986107. View

Kaneko T, Fujiyama F . Complementary distribution of vesicular glutamate transporters in the central nervous system. Neurosci Res. 2002; 42(4):243-50. DOI: 10.1016/s0168-0102(02)00009-3. View

Hioki H, Nakamura H, Ma Y, Konno M, Hayakawa T, Nakamura K . Vesicular glutamate transporter 3-expressing nonserotonergic projection neurons constitute a subregion in the rat midbrain raphe nuclei. J Comp Neurol. 2009; 518(5):668-86. DOI: 10.1002/cne.22237. View

Gras C, Amilhon B, Lepicard E, Poirel O, Vinatier J, Herbin M . The vesicular glutamate transporter VGLUT3 synergizes striatal acetylcholine tone. Nat Neurosci. 2008; 11(3):292-300. DOI: 10.1038/nn2052. View

Favier M, Pietrancosta N, El Mestikawy S, Gangarossa G . Leveraging VGLUT3 Functions to Untangle Brain Dysfunctions. Trends Pharmacol Sci. 2021; 42(6):475-490. DOI: 10.1016/j.tips.2021.03.003. View

Martineau M, Guzman R, Fahlke C, Klingauf J . VGLUT1 functions as a glutamate/proton exchanger with chloride channel activity in hippocampal glutamatergic synapses. Nat Commun. 2017; 8(1):2279. PMC: 5741633. DOI: 10.1038/s41467-017-02367-6. View

Mendez J, Bourque M, Bo G, Bourdeau M, Danik M, Williams S . Developmental and target-dependent regulation of vesicular glutamate transporter expression by dopamine neurons. J Neurosci. 2008; 28(25):6309-18. PMC: 6670902. DOI: 10.1523/JNEUROSCI.1331-08.2008. View

Orieux G, Francois C, Feger J, Yelnik J, Vila M, Ruberg M . Metabolic activity of excitatory parafascicular and pedunculopontine inputs to the subthalamic nucleus in a rat model of Parkinson's disease. Neuroscience. 2000; 97(1):79-88. DOI: 10.1016/s0306-4522(00)00011-7. View

10.

Shigeri Y, Seal R, Shimamoto K . Molecular pharmacology of glutamate transporters, EAATs and VGLUTs. Brain Res Brain Res Rev. 2004; 45(3):250-65. DOI: 10.1016/j.brainresrev.2004.04.004. View

11.

McKinley J, Shi Z, Kawikova I, Hur M, Bamford I, Priya Sudarsana Devi S . Dopamine Deficiency Reduces Striatal Cholinergic Interneuron Function in Models of Parkinson's Disease. Neuron. 2019; 103(6):1056-1072.e6. PMC: 7102938. DOI: 10.1016/j.neuron.2019.06.013. View

12.

Chen I, Pant S, Wu Q, Cater R, Sobti M, Vandenberg R . Glutamate transporters have a chloride channel with two hydrophobic gates. Nature. 2021; 591(7849):327-331. PMC: 7954978. DOI: 10.1038/s41586-021-03240-9. View

13.

Plaitakis A, Shashidharan P . Glutamate transport and metabolism in dopaminergic neurons of substantia nigra: implications for the pathogenesis of Parkinson's disease. J Neurol. 2000; 247 Suppl 2:II25-35. DOI: 10.1007/pl00007757. View

14.

Yamaguchi T, Qi J, Wang H, Zhang S, Morales M . Glutamatergic and dopaminergic neurons in the mouse ventral tegmental area. Eur J Neurosci. 2015; 41(6):760-72. PMC: 4363208. DOI: 10.1111/ejn.12818. View

15.

Schafer M, Varoqui H, Defamie N, Weihe E, Erickson J . Molecular cloning and functional identification of mouse vesicular glutamate transporter 3 and its expression in subsets of novel excitatory neurons. J Biol Chem. 2002; 277(52):50734-48. DOI: 10.1074/jbc.M206738200. View

16.

Steinkellner T, Conrad W, Kovacs I, Rissman R, Lee E, Trojanowski J . Dopamine neurons exhibit emergent glutamatergic identity in Parkinson's disease. Brain. 2022; 145(3):879-886. PMC: 9050538. DOI: 10.1093/brain/awab373. View

17.

Wang Y, Wang Y, Liu J, Wang X . Electroacupuncture Alleviates Motor Symptoms and Up-Regulates Vesicular Glutamatergic Transporter 1 Expression in the Subthalamic Nucleus in a Unilateral 6-Hydroxydopamine-Lesioned Hemi-Parkinsonian Rat Model. Neurosci Bull. 2018; 34(3):476-484. PMC: 5960449. DOI: 10.1007/s12264-018-0213-y. View

18.

Magi S, Piccirillo S, Amoroso S, Lariccia V . Excitatory Amino Acid Transporters (EAATs): Glutamate Transport and Beyond. Int J Mol Sci. 2019; 20(22). PMC: 6888595. DOI: 10.3390/ijms20225674. View

19.

Buck S, Erickson-Oberg M, Bhatte S, McKellar C, Ramanathan V, Rubin S . Roles of VGLUT2 and Dopamine/Glutamate Co-Transmission in Selective Vulnerability to Dopamine Neurodegeneration. ACS Chem Neurosci. 2022; 13(2):187-193. PMC: 9242677. DOI: 10.1021/acschemneuro.1c00741. View

20.

Gangarossa G, Guzman M, Prado V, Prado M, Daumas S, El Mestikawy S . Role of the atypical vesicular glutamate transporter VGLUT3 in l-DOPA-induced dyskinesia. Neurobiol Dis. 2015; 87:69-79. DOI: 10.1016/j.nbd.2015.12.010. View