Search

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.