Regulation Of Glutamate Receptors By Striatal-Enriched Tyrosine Phosphatase 61 (Step61)

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, STEP61, 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, STEP61 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 STEP61 differentially regulates NMDARs and AMPARs, as well as its role in plasticity and disease.