PRRT2 modulates presynaptic Ca2+ influx by interacting with P/Q-type channels
Summary: Loss-of-function mutations in proline-rich transmembrane protein-2 (PRRT2) cause paroxysmal disorders associated with defective Ca2+ dependence of glutamatergic transmission. We find that either acute or constitutive PRRT2 deletion induces a significant decrease in the amplitude of evoked e...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-06-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124721006136 |
| _version_ | 1819012455980859392 |
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| author | Daniele Ferrante Bruno Sterlini Cosimo Prestigio Antonella Marte Anna Corradi Franco Onofri Giorgio Tortarolo Giuseppe Vicidomini Andrea Petretto Jessica Muià Agnes Thalhammer Pierluigi Valente Lorenzo A. Cingolani Fabio Benfenati Pietro Baldelli |
| author_facet | Daniele Ferrante Bruno Sterlini Cosimo Prestigio Antonella Marte Anna Corradi Franco Onofri Giorgio Tortarolo Giuseppe Vicidomini Andrea Petretto Jessica Muià Agnes Thalhammer Pierluigi Valente Lorenzo A. Cingolani Fabio Benfenati Pietro Baldelli |
| author_sort | Daniele Ferrante |
| collection | DOAJ |
| description | Summary: Loss-of-function mutations in proline-rich transmembrane protein-2 (PRRT2) cause paroxysmal disorders associated with defective Ca2+ dependence of glutamatergic transmission. We find that either acute or constitutive PRRT2 deletion induces a significant decrease in the amplitude of evoked excitatory postsynaptic currents (eEPSCs) that is insensitive to extracellular Ca2+ and associated with a reduced contribution of P/Q-type Ca2+ channels to the EPSC amplitude. This synaptic phenotype parallels a decrease in somatic P/Q-type Ca2+ currents due to a decreased membrane targeting of the channel with unchanged total expression levels. Co-immunoprecipitation, pull-down assays, and proteomics reveal a specific and direct interaction of PRRT2 with P/Q-type Ca2+ channels. At presynaptic terminals lacking PRRT2, P/Q-type Ca2+ channels reduce their clustering at the active zone, with a corresponding decrease in the P/Q-dependent presynaptic Ca2+ signal. The data highlight the central role of PRRT2 in ensuring the physiological Ca2+ sensitivity of the release machinery at glutamatergic synapses. |
| first_indexed | 2024-12-21T01:44:20Z |
| format | Article |
| id | doaj.art-6a130e3a58d54960b3694a3944741bd1 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-21T01:44:20Z |
| publishDate | 2021-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-6a130e3a58d54960b3694a3944741bd12022-12-21T19:20:04ZengElsevierCell Reports2211-12472021-06-013511109248PRRT2 modulates presynaptic Ca2+ influx by interacting with P/Q-type channelsDaniele Ferrante0Bruno Sterlini1Cosimo Prestigio2Antonella Marte3Anna Corradi4Franco Onofri5Giorgio Tortarolo6Giuseppe Vicidomini7Andrea Petretto8Jessica Muià9Agnes Thalhammer10Pierluigi Valente11Lorenzo A. Cingolani12Fabio Benfenati13Pietro Baldelli14Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, ItalyDepartment 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, ItalyDepartment of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, ItalyDepartment of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy; IRCCS, Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, ItalyDepartment of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy; IRCCS, Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, ItalyDepartment of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy; IRCCS, Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, ItalyMolecular Microscopy and Spectroscopy, Istituto Italiano di Tecnologia, Via Enrico Melen, 83B, 16152, Genova, ItalyMolecular Microscopy and Spectroscopy, Istituto Italiano di Tecnologia, Via Enrico Melen, 83B, 16152, Genova, ItalyCore Facilities-Clinical Proteomics and Metabolomics, IRCCS, Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genova, ItalyDepartment 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, ItalyCenter for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, ItalyDepartment of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy; IRCCS, Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, ItalyCenter for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy; Department of Life Sciences, University of Trieste, Trieste, ItalyCenter for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy; IRCCS, Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy; Corresponding authorDepartment of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy; IRCCS, Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy; Corresponding authorSummary: Loss-of-function mutations in proline-rich transmembrane protein-2 (PRRT2) cause paroxysmal disorders associated with defective Ca2+ dependence of glutamatergic transmission. We find that either acute or constitutive PRRT2 deletion induces a significant decrease in the amplitude of evoked excitatory postsynaptic currents (eEPSCs) that is insensitive to extracellular Ca2+ and associated with a reduced contribution of P/Q-type Ca2+ channels to the EPSC amplitude. This synaptic phenotype parallels a decrease in somatic P/Q-type Ca2+ currents due to a decreased membrane targeting of the channel with unchanged total expression levels. Co-immunoprecipitation, pull-down assays, and proteomics reveal a specific and direct interaction of PRRT2 with P/Q-type Ca2+ channels. At presynaptic terminals lacking PRRT2, P/Q-type Ca2+ channels reduce their clustering at the active zone, with a corresponding decrease in the P/Q-dependent presynaptic Ca2+ signal. The data highlight the central role of PRRT2 in ensuring the physiological Ca2+ sensitivity of the release machinery at glutamatergic synapses.http://www.sciencedirect.com/science/article/pii/S2211124721006136excitatory synaptic transmissionsynchronous neurotransmitter releaseSNARE complexvoltage-gated Ca2+ channelsP/Q-type Ca2+ channelschannel trafficking |
| spellingShingle | Daniele Ferrante Bruno Sterlini Cosimo Prestigio Antonella Marte Anna Corradi Franco Onofri Giorgio Tortarolo Giuseppe Vicidomini Andrea Petretto Jessica Muià Agnes Thalhammer Pierluigi Valente Lorenzo A. Cingolani Fabio Benfenati Pietro Baldelli PRRT2 modulates presynaptic Ca2+ influx by interacting with P/Q-type channels Cell Reports excitatory synaptic transmission synchronous neurotransmitter release SNARE complex voltage-gated Ca2+ channels P/Q-type Ca2+ channels channel trafficking |
| title | PRRT2 modulates presynaptic Ca2+ influx by interacting with P/Q-type channels |
| title_full | PRRT2 modulates presynaptic Ca2+ influx by interacting with P/Q-type channels |
| title_fullStr | PRRT2 modulates presynaptic Ca2+ influx by interacting with P/Q-type channels |
| title_full_unstemmed | PRRT2 modulates presynaptic Ca2+ influx by interacting with P/Q-type channels |
| title_short | PRRT2 modulates presynaptic Ca2+ influx by interacting with P/Q-type channels |
| title_sort | prrt2 modulates presynaptic ca2 influx by interacting with p q type channels |
| topic | excitatory synaptic transmission synchronous neurotransmitter release SNARE complex voltage-gated Ca2+ channels P/Q-type Ca2+ channels channel trafficking |
| url | http://www.sciencedirect.com/science/article/pii/S2211124721006136 |
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