Exogenous alpha-Synuclein decreases raft partitioning of Cav2.2 channels inducing dopamine release

Ronzitti, G., Bucci, G., Emanuele, M., Leo, D., Sotnikova, T. D., Mus, L. V., Soubrane, C. H., Dallas, M. L. ORCID: https://orcid.org/0000-0002-5190-0522, Thalhammer, A., Cingolani, L. A., Mochida, S., Gainetdinov, R. R., Stephens, G. J. ORCID: https://orcid.org/0000-0002-8966-4238 and Chieregatti, E. (2014) Exogenous alpha-Synuclein decreases raft partitioning of Cav2.2 channels inducing dopamine release. Journal of Neuroscience, 34 (32). pp. 10603-10615. ISSN 1529-2401 doi: 10.1523/JNEUROSCI.0608-14.2014

Abstract/Summary

alpha-Synuclein is thought to regulate neurotransmitter release through multiple interactions with presynaptic proteins, cytoskeletal elements, ion channels, and synaptic vesicles membrane. alpha-Synuclein is abundant in the presynaptic compartment, and its release from neurons and glia has been described as responsible for spreading of alpha-synuclein-derived pathology. alpha-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 alpha-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 alpha-synuclein into the striatum also leads to acute dopamine release. We further demonstrate that alpha-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 alpha-synuclein acts from the extracellular milieu to modulate neurotransmitter release and propose a unifying hypothesis for the mechanism of alpha-synuclein action on multiple targets: the reorganization of plasma membrane microdomains.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/37399
Identification Number/DOI	10.1523/JNEUROSCI.0608-14.2014
Refereed	Yes
Divisions	Interdisciplinary Research Centres (IDRCs) > Centre for Integrative Neuroscience and Neurodynamics (CINN) Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
Publisher	Society for Neuroscience
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