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

Pierluigi Valente; Enrico Castroflorio; Pia Rossi; Manuela Fadda; Bruno Sterlini; Romina Ines Cervigni; Cosimo Prestigio; Silvia Giovedì; Franco Onofri; Elisa Mura; Fabrizia C. Guarnieri; Antonella Marte; Marta Orlando; Federico Zara; Anna Fassio; Flavia Valtorta; Pietro Baldelli; Anna Corradi; Fabio Benfenati

doi:10.1016/j.celrep.2016.03.005

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

Pierluigi Valente, Enrico Castroflorio, Pia Rossi, Manuela Fadda, Bruno Sterlini, Romina Ines Cervigni, Cosimo Prestigio, Silvia Giovedì, Franco Onofri, Elisa Mura, Fabrizia C. Guarnieri, Antonella Marte, Marta Orlando, Federico Zara, Anna Fassio, Flavia Valtorta, Pietro Baldelli, Anna Corradi, Fabio Benfenati

Istituto "Giannina Gaslini"

Research output: Contribution to journal › Article › peer-review

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 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.

Original language	English
Pages (from-to)	117-131
Number of pages	15
Journal	Cell Reports
Volume	15
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2016.03.005
Publication status	Published - Apr 5 2016

Keywords

Knockdown
PRRT2
Release probability
Synaptic transmission
Synaptotagmin
Synchronous and asynchronous release

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

Access to Document

10.1016/j.celrep.2016.03.005

Cite this

Valente, P., Castroflorio, E., Rossi, P., Fadda, M., Sterlini, B., Cervigni, R. I., Prestigio, C., Giovedì, S., Onofri, F., Mura, E., Guarnieri, F. C., Marte, A., Orlando, M., Zara, F., Fassio, A., Valtorta, F., Baldelli, P., Corradi, A., & Benfenati, F. (2016). PRRT2 Is a Key Component of the Ca²⁺-Dependent Neurotransmitter Release Machinery. Cell Reports, 15(1), 117-131. https://doi.org/10.1016/j.celrep.2016.03.005

Valente, P, Castroflorio, E, Rossi, P, Fadda, M, Sterlini, B, Cervigni, RI, Prestigio, C, Giovedì, S, Onofri, F, Mura, E, Guarnieri, FC, Marte, A, Orlando, M, Zara, F, Fassio, A, Valtorta, F, Baldelli, P, Corradi, A & Benfenati, F 2016, 'PRRT2 Is a Key Component of the Ca²⁺-Dependent Neurotransmitter Release Machinery', Cell Reports, vol. 15, no. 1, pp. 117-131. https://doi.org/10.1016/j.celrep.2016.03.005

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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 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.",

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AU - Valente, Pierluigi

AU - Castroflorio, Enrico

AU - Rossi, Pia

AU - Fadda, Manuela

AU - Sterlini, Bruno

AU - Cervigni, Romina Ines

AU - Prestigio, Cosimo

AU - Giovedì, Silvia

AU - Onofri, Franco

AU - Mura, Elisa

AU - Guarnieri, Fabrizia C.

AU - Marte, Antonella

AU - Orlando, Marta

AU - Zara, Federico

AU - Fassio, Anna

AU - Valtorta, Flavia

AU - Baldelli, Pietro

AU - Corradi, Anna

AU - Benfenati, Fabio

PY - 2016/4/5

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N2 - 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.

AB - 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.

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