Referenced in: none

Automatically associated channels: Cav2.2

Title: Exogenous α-synuclein decreases raft partitioning of Cav2.2 channels inducing dopamine release.

Authors: Giuseppe Ronzitti, Giovanna Bucci, Marco Emanuele, Damiana Leo, Tatyana D Sotnikova, Liudmila V Mus, Camille H Soubrane, Mark L Dallas, Agnes Thalhammer, Lorenzo A Cingolani, Sumiko Mochida, Raul R Gainetdinov, Gary J Stephens, Evelina Chieregatti

Journal, date & volume: J. Neurosci., 2014 Aug 6 , 34, 10603-15

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25100594

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.