PRRT2 modulates presynaptic Ca2+ influx by interacting with P/Q-type channels

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number109248
JournalCell Reports
Volume35
Issue number11
DOIs
Publication statusPublished - Jun 15 2021

Keywords

  • active zone
  • channel trafficking
  • excitatory synaptic transmission
  • nerve terminals
  • P/Q-type Ca channels
  • probability of release
  • PRRT2-linked paroxysmal disorders
  • SNARE complex
  • synchronous neurotransmitter release
  • voltage-gated Ca channels

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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