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Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific protein phosphatase that regulates a variety of synaptic proteins, including NMDA receptors (NAMDRs). To better understand STEP’s effect on other receptors, we used mass spectrometry to identify the STEP(61) interactome. We identified a number of known interactors, but also ones including the GluA2 subunit of AMPA receptors (AMPARs). We show that STEP(61) binds to the C termini of GluA2 and GluA3 as well as endogenous AMPARs in hippocampus. The synaptic expression of GluA2 and GluA3 is increased in STEP-KO mouse brain, and STEP knockdown in hippocampal slices increases AMPAR-mediated synaptic currents. Interestingly, STEP(61) overexpression reduces the synaptic expression and synaptic currents of both AMPARs and NMDARs. Furthermore, STEP(61) regulation of synaptic AMPARs is mediated by lysosomal degradation. Thus, we report a comprehensive list of STEP(61) binding partners, including AMPARs, and reveal a central role for STEP(61) in differentially organizing synaptic AMPARs and NMDARs. |
