PRRT2 modulates presynaptic Ca2+ 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. • PRRT2 deficiency reduces the contribution of P/Q-type Ca 2+ channels to the EPSC • PRRT2 deficiency decreases P/Q-type currents and membrane targeting of the channels • PRRT2 directly interacts with P/Q-type Ca 2+ channels • PRRT2 deficiency reduces P/Q-channel clustering and Ca 2+ signals in nerve terminals PRRT2 deficiency causes paroxysmal disorders associated with defective Ca 2+ dependence of glutamatergic transmission. Ferrante et al. now find that, in the absence of PRRT2, the membrane targeting of P/Q-type Ca 2+ channels is reduced, and the channels fail to concentrate at the nanodomain where the machinery for synchronous release is assembled.