title: PRRT2 Is a Key Component of the Ca(2+)-Dependent Neurotransmitter Release Machinery.
abstract: 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 Ca(2+) 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 Ca(2+)-sensing machinery and that it plays an important role in the final steps of neurotransmitter release.
authors.affiliation: Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Valente
authors.affiliation: Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy; Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Castroflorio
authors.affiliation: Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy.
authors.forename: Pia
authors.initials: P
authors.lastname: Rossi
authors.affiliation: Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Fadda
authors.affiliation: Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy; Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Sterlini
authors.affiliation: San Raffaele Scientific Institute and Vita Salute University, Via Olgettina 58, 20132 Milano, Italy.
authors.forename: Romina Ines
authors.initials: RI
authors.lastname: Cervigni
authors.affiliation: Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy; Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy.
authors.forename: Cosimo
authors.initials: C
authors.lastname: Prestigio
authors.affiliation: Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Giovedì
authors.affiliation: Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Onofri
authors.affiliation: San Raffaele Scientific Institute and Vita Salute University, Via Olgettina 58, 20132 Milano, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Mura
authors.affiliation: San Raffaele Scientific Institute and Vita Salute University, Via Olgettina 58, 20132 Milano, Italy.
authors.forename: Fabrizia C
authors.initials: FC
authors.lastname: Guarnieri
authors.affiliation: Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Marte
authors.affiliation: Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Orlando
authors.affiliation: Department of Neuroscience, Istituto Giannina Gaslini, Via Gerolamo Gaslini, 5, 16148 Genova, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Zara
authors.affiliation: Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy; Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Fassio
authors.affiliation: San Raffaele Scientific Institute and Vita Salute University, Via Olgettina 58, 20132 Milano, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Valtorta
authors.affiliation: Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy; Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Baldelli
authors.affiliation: Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Corradi
authors.affiliation: Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy; Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy. Electronic address: fabio.benfenati@iit.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Benfenati
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D002478:Cells, Cultured; D005089:Exocytosis; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018377:Neurotransmitter Agents / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055366:Synaptic Potentials; D013572:Synaptic Vesicles / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D050857:Synaptotagmins / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D018377:Neurotransmitter Agents; C000609581:PRRT2 protein, mouse; D050825:Synaptosomal-Associated Protein 25; D050857:Synaptotagmins
keywords: PRRT2; knockdown; release probability; synaptic transmission; synaptotagmin; synchronous and asynchronous release