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 Ca2+ dependence of glutamatergic transmission. We found that either acute or constitutive PRRT2 deletion induced a significant decrease in the amplitude of evoked excitatory postsynaptic currents (eEPSCs) that was insensitive to extracellular Ca2+ and associated with a reduced contribution of P/Q-type Ca2+ channels to the EPSC amplitude. This synaptic phenotype was paralleled by a decrease of somatic P/Q-type Ca2+ currents due to a decreased membrane targeting of the channel with unchanged total expression levels. Co-immunoprecipitation assays and proteomic screens revealed an interaction between PRRT2 and 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 of the P/Q-dependent presynaptic Ca2+ signal. The data highlight the central role of PRRT2 in assuring the physiological Ca2+ sensitivity of the release machinery at glutamatergic synapses.