title: Exogenous α-synuclein decreases raft partitioning of Cav2.2 channels inducing dopamine release.
abstract: α-Synuclein is thought to regulate neurotransmitter release through multiple interactions with presynaptic proteins, cytoskeletal elements, ion channels, and synaptic vesicles membrane. α-Synuclein is abundant in the presynaptic compartment, and its release from neurons and glia has been described as responsible for spreading of α-synuclein-derived pathology. α-Synuclein-dependent dysregulation of neurotransmitter release might occur via its action on surface-exposed calcium channels. Here, we provide electrophysiological and biochemical evidence to show that α-synuclein, applied to rat neurons in culture or striatal slices, selectively activates Cav2.2 channels, and said activation correlates with increased neurotransmitter release. Furthermore, in vivo perfusion of α-synuclein into the striatum also leads to acute dopamine release. We further demonstrate that α-synuclein reduces the amount of plasma membrane cholesterol and alters the partitioning of Cav2.2 channels, which move from raft to cholesterol-poor areas of the plasma membrane. We provide evidence for a novel mechanism through which α-synuclein acts from the extracellular milieu to modulate neurotransmitter release and propose a unifying hypothesis for the mechanism of α-synuclein action on multiple targets: the reorganization of plasma membrane microdomains.
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163, Genoa, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ronzitti
authors.affiliation: School of Pharmacy, University of Reading, Whiteknights, Reading, RG6 6AJ, United Kingdom.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bucci
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163, Genoa, Italy.
authors.forename: Marco
authors.identifier: http://orcid.org/0000-0001-6964-2026
authors.initials: M
authors.lastname: Emanuele
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163, Genoa, Italy.
authors.forename: Damiana
authors.initials: D
authors.lastname: Leo
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163, Genoa, Italy.
authors.forename: Tatyana D
authors.initials: TD
authors.lastname: Sotnikova
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163, Genoa, Italy.
authors.forename: Liudmila V
authors.initials: LV
authors.lastname: Mus
authors.affiliation: School of Pharmacy, University of Reading, Whiteknights, Reading, RG6 6AJ, United Kingdom.
authors.forename: Camille H
authors.initials: CH
authors.lastname: Soubrane
authors.affiliation: School of Pharmacy, University of Reading, Whiteknights, Reading, RG6 6AJ, United Kingdom.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Dallas
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163, Genoa, Italy.
authors.forename: Agnes
authors.initials: A
authors.lastname: Thalhammer
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163, Genoa, Italy.
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Cingolani
authors.affiliation: Department of Physiology, Tokyo Medical University, Tokyo 160-8402, Japan and.
authors.forename: Sumiko
authors.initials: S
authors.lastname: Mochida
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163, Genoa, Italy, Skolkovo Institute of Science and Technology Skolkovo, Moscow region, 143025 and Faculty of Biology and Soil Science, St. Petersburg State University, St. Petersburg, 199034, Russia.
authors.forename: Raul R
authors.initials: RR
authors.lastname: Gainetdinov
authors.affiliation: School of Pharmacy, University of Reading, Whiteknights, Reading, RG6 6AJ, United Kingdom.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Stephens
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163, Genoa, Italy, evelina.chieregatti@iit.it.
authors.forename: Evelina
authors.initials: E
authors.lastname: Chieregatti
mesh_terms: D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004298:Dopamine / Q000378:metabolism*; D004622:Embryo, Mammalian; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D008297:Male; D021962:Membrane Microdomains / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers / Q000494:pharmacology; D017783:Superior Cervical Ganglion / Q000166:cytology; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D016708:Synaptophysin / Q000378:metabolism; D014966:Xanthenes / Q000378:metabolism; D051844:alpha-Synuclein / Q000494:pharmacology*
chemical_list: D000814:Aniline Compounds; D000906:Antibodies; C503279:Cacna1b protein, rat; D020864:Calcium Channels, N-Type; C409648:Fluo 4; D026941:Sodium Channel Blockers; D016708:Synaptophysin; D014966:Xanthenes; D051844:alpha-Synuclein; D004298:Dopamine
keywords: Cav2.2 channels; dopamine release; extracellular alpha-synuclein; lipid rafts
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