PRRT2 Is a Key Component of the Ca2+-Dependent Neurotransmitter Release Machinery

• Published in: Cell reports (Cambridge) Vol. 15; no. 1; pp. 117 - 131
• Main Authors: Valente, Pierluigi, Castroflorio, Enrico, Rossi, Pia, Fadda, Manuela, Sterlini, Bruno, Cervigni, Romina Ines, Prestigio, Cosimo, Giovedì, Silvia, Onofri, Franco, Mura, Elisa, Guarnieri, Fabrizia C., Marte, Antonella, Orlando, Marta, Zara, Federico, Fassio, Anna, Valtorta, Flavia, Baldelli, Pietro, Corradi, Anna, Benfenati, Fabio
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 05.04.2016; Cell Press; Elsevier
• Subjects: knockdown; PRRT2; release probability; synaptic transmission; synaptotagmin; synchronous and asynchronous release; synchronous and asynchronous release; synaptic transmission; PRRT2; synaptotagmin; knockdown; release probability
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.03.005

Heterozygous mutations in proline-rich transmembrane protein 2 (PRRT2) underlie a group of paroxysmal disorders, including epilepsy, kinesigenic dyskinesia, and migraine. Most of the mutations lead to impaired PRRT2 expression, suggesting that loss of PRRT2 function may contribute to pathogenesis. We show that PRRT2 is enriched in presynaptic terminals and that its silencing decreases the number of synapses and increases the number of docked synaptic vesicles at rest. PRRT2-silenced neurons exhibit a severe impairment of synchronous release, attributable to a sharp decrease in release probability and Ca2+ sensitivity and associated with a marked increase of the asynchronous/synchronous release ratio. PRRT2 interacts with the synaptic proteins SNAP-25 and synaptotagmin 1/2. The results indicate that PRRT2 is intimately connected with the Ca2+-sensing machinery and that it plays an important role in the final steps of neurotransmitter release. [Display omitted] •PRRT2 is a presynaptic protein•PRRT2 is required for synchronous neurotransmitter release•PRRT2 silencing decreases synaptic density and release probability•PRRT2 interacts with the fast Ca2+ sensors synaptotagmin 1/2 Valente et al. show that PRRT2, a single causative gene for a group of paroxysmal neurological diseases, is a key component of regulated exocytosis. Silencing PRRT2 dramatically impairs neurotransmitter release by markedly reducing release probability. PRRT2 interacts with the fast Ca2+ sensors synaptotagmin 1/2 and endows the SNARE complex with Ca2+ sensitivity.