PRRT2 modulates presynaptic Ca2+ influx by interacting with P/Q-type channels

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.

Keywords: P/Q-type Ca(2+) channels; PRRT2-linked paroxysmal disorders; SNARE complex; active zone; channel trafficking; excitatory synaptic transmission; nerve terminals; probability of release; synchronous neurotransmitter release; voltage-gated Ca(2+) channels.