The STEP₆₁ interactome reveals subunit-specific AMPA receptor binding and synaptic regulation

Area of Science:

• Neuroscience
• Molecular Biology
• Synaptic Plasticity

Background:

• Striatal-enriched protein tyrosine phosphatase (STEP) is a key regulator of synaptic function.
• STEP influences NMDA receptor (NMDAR) activity, but its role in other synaptic receptors is less understood.

Purpose of the Study:

• To identify novel STEP binding partners using mass spectrometry.
• To elucidate the role of STEP61 in regulating AMPA receptors (AMPARs) and their synaptic function.

Main Methods:

• Mass spectrometry was used to identify the STEP61 interactome.
• Western blotting and co-immunoprecipitation were employed to confirm interactions.
• Electrophysiological recordings were performed in hippocampal slices from STEP knockout (STEP-KO) and wild-type mice.

Main Results:

• STEP61 was identified to bind the GluA2 and GluA3 subunits of AMPARs.
• Synaptic expression of GluA2 and GluA3, and AMPAR-mediated currents, were increased in STEP-KO mice.
• STEP61 overexpression decreased synaptic AMPAR and NMDAR expression and function.
• STEP61-mediated regulation of synaptic AMPARs involves lysosomal degradation.

Conclusions:

• STEP61 directly interacts with and regulates AMPARs, in addition to NMDARs.
• STEP61 plays a critical role in controlling the synaptic abundance and function of both AMPARs and NMDARs.
• STEP61 differentially organizes synaptic AMPARs and NMDARs through mechanisms including lysosomal degradation.