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 (see publication in Journal )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.