RT Journal Article SR Electronic T1 Exogenous α-Synuclein Decreases Raft Partitioning of Cav2.2 Channels Inducing Dopamine Release JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 10603 OP 10615 DO 10.1523/JNEUROSCI.0608-14.2014 VO 34 IS 32 A1 Giuseppe Ronzitti A1 Giovanna Bucci A1 Marco Emanuele A1 Damiana Leo A1 Tatyana D. Sotnikova A1 Liudmila V. Mus A1 Camille H. Soubrane A1 Mark L. Dallas A1 Agnes Thalhammer A1 Lorenzo A. Cingolani A1 Sumiko Mochida A1 Raul R. Gainetdinov A1 Gary J. Stephens A1 Evelina Chieregatti YR 2014 UL http://www.jneurosci.org/content/34/32/10603.abstract AB 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.