PRRT2 modulates presynaptic Ca(2+) influx by interacting with P/Q-type channels

Loss-of-function mutations in proline-rich transmembrane protein-2 (PRRT2) cause paroxysmal disorders associated with defective Ca(2+) 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 Ca(2+) and associated with a reduced contribution of P/Q-type Ca(2+) channels to the EPSC amplitude. This synaptic phenotype parallels a decrease in somatic P/Q-type Ca(2+) 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 Ca(2+) channels. At presynaptic terminals lacking PRRT2, P/Q-type Ca(2+) channels reduce their clustering at the active zone, with a corresponding decrease in the P/Q-dependent presynaptic Ca(2+) signal. The data highlight the central role of PRRT2 in ensuring the physiological Ca(2+) sensitivity of the release machinery at glutamatergic synapses.