Regulation of glutamate receptors by striatal-enriched tyrosine phosphatase 61 (STEP ).

Phosphorylation regulates glutamate receptor trafficking. The cytosolic C-terminal domains of both NMDA receptors (NMDARs) and AMPA receptors (AMPARs) have distinct motifs, which are substrates for serine/threonine and tyrosine phosphorylation. Decades of research have shown how phosphorylation of glutamate receptors mediates protein binding and receptor trafficking, ultimately controlling synaptic transmission and plasticity. STEP is a protein tyrosine phosphatase (also known as PTPN5), with several isoforms resulting from alternative splicing. Targets of STEP include a variety of important synaptic substrates, among which are the tyrosine kinase Fyn and glutamate receptors. In particular, STEP , the longest isoform, dephosphorylates the NMDAR subunit GluN2B and strongly regulates the expression of NMDARs at synapses. This interplay between STEP, Fyn and GluN2B-containing NMDARs has been characterized by multiple groups. More recently, STEP was shown to bind to AMPARs in a subunit-specific manner and differentially regulate synaptic NMDARs and AMPARs. Because of its many effects on synaptic proteins, STEP has been implicated in regulating excitatory synapses during plasticity and playing a role in synaptic dysfunction in a variety of neurological disorders. In this review, we will highlight the ways in which STEP differentially regulates NMDARs and AMPARs, as well as its role in plasticity and disease.