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

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Loss-of-function mutations in proline-rich transmembrane protein-2 (PRRT2) are linked to paroxysmal disorders.
• These disorders involve impaired calcium (Ca2+) dependence in glutamatergic neurotransmission.

Purpose of the Study:

• To investigate the role of PRRT2 in regulating synaptic transmission and calcium channel function.
• To elucidate the molecular mechanisms underlying PRRT2's function at glutamatergic synapses.

Main Methods:

• Utilized acute and constitutive PRRT2 deletion models.
• Performed electrophysiological recordings to measure excitatory postsynaptic currents (eEPSCs).
• Employed co-immunoprecipitation, pull-down assays, and proteomics to identify protein interactions.

Main Results:

• PRRT2 deletion decreased eEPSC amplitude, independent of extracellular Ca2+.
• Reduced contribution of P/Q-type Ca2+ channels to synaptic currents was observed.
• PRRT2 directly interacts with P/Q-type Ca2+ channels, affecting their presynaptic terminal clustering and Ca2+ signaling.

Conclusions:

• PRRT2 is crucial for maintaining the physiological Ca2+ sensitivity of the release machinery at glutamatergic synapses.
• PRRT2's interaction with P/Q-type Ca2+ channels is essential for their proper localization and function.