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

Abstract

Summary 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.

A Push–Pull Mechanism Between PRRT2 and β4-subunit Differentially Regulates Membrane Exposure and Biophysical Properties of NaV1.2 Sodium Channels

“…Structurally, PRRT2 is a neuron-specific type 2 integral membrane protein with a large cytosolic N-terminal domain [9], expressed in the axonal and presynaptic domains [10]. At the presynaptic level, PRRT2 orchestrates the Ca 2+ sensitivity of synaptic vesicle exocytosis and by interacting with the SNARE complex, synaptotagmins 1/2, P/Q-type voltage-gated Ca 2+ channels (Ca V ), and the actin cytoskeleton [10][11][12][13][14]. At this level, PRRT2 enhances the probability of release to single stimuli and favors synaptic depression during sustained activity [10,14,15].…”

“…At the presynaptic level, PRRT2 orchestrates the Ca 2+ sensitivity of synaptic vesicle exocytosis and by interacting with the SNARE complex, synaptotagmins 1/2, P/Q-type voltage-gated Ca 2+ channels (Ca V ), and the actin cytoskeleton [ 10 – 14 ]. At this level, PRRT2 enhances the probability of release to single stimuli and favors synaptic depression during sustained activity [ 10 , 14 , 15 ].…”

Rescue of neuropsychiatric phenotypes in a mouse model of 16p11.2 duplication syndrome by genetic correction of an epilepsy network hub

“…It is therefore likely that post-transcriptional effects regulating protein abundance and localization are involved. Given that PRRT2 has been show to regulate surface trafficking of membrane proteins 48 , 49 , and that it interacts with an abundance of proteins that are dysregulated, we would propose that PRRT2-dependent membrane trafficking could be an important player in remodeling the membrane proteome of 16p11.2 dup/+ mice.…”

CRISPR-mediated activation of autism gene Itgb3 restores cortical network excitability via mGluR5 signaling

“…Cortical neuronal cultures were prepared from P0 Itgb3 +/+ (WT), Itgb3 +/− (Het), or Itgb3 −/− (KO) pups as previously described, 88 , 89 with minor modifications. Briefly, cortices were dissected in ice-cold HBSS, digested with papain (30 U; cat.…”