Regulation of NMDA receptor trafficking and function by striatal‐enriched tyrosine phosphatase (STEP)

Abstract

Regulation of N-methyl-D-aspartate (NMDA) receptors is critical for the normal functioning of the central nervous system. There must be precise mechanisms to allow for changes in receptor function required for learning and normal synaptic transmission, but within tight constraints to prevent pathology. Tyrosine phosphorylation is a major means by which NMDA receptors are regulated through the equilibrium between activity of Src family kinases and tyrosine phosphatases. Identification of NMDA receptor phosphatases has been difficult, the best candidate being striatal-enriched tyrosine phosphatase (STEP). Here we demonstrate that STEP is a critical regulator of NMDA receptors and reveal that the action of this tyrosine phosphatase controls the constitutive trafficking of NMDA receptors and leads to changes in NMDA receptor activity at the neuronal surface. We show that STEP binds directly to NMDA receptors in the absence of other synaptic proteins. The activity of STEP selectively affects the expression of NMDA receptors at the neuronal plasma membrane. The result of STEP's action upon the NMDA receptor affects the functional properties of the receptor and its downstream signaling. These effects are evident when STEP levels are chronically reduced, indicating that there is no redundancy amongst phosphatases to compensate for altered STEP function in the CNS. STEP may have evolved specifically to fill a pivotal role as the NMDA receptor phosphatase, having a distinct and restricted localization and compartmentalization, and unique activity towards the NMDA receptor and its signaling pathway.

A Critical Role for Protein Tyrosine Phosphatase Nonreceptor Type 5 in Determining Individual Susceptibility to Develop Stress-Related Cognitive and Morphological Changes

“…In cultured cortical neurons, knockdown of PTPN5 levels by RNA interference has been shown to increase surface expression of NR1, NR2A, and NR2B subunits of NMDA receptors, but not GluR1 subunit of AMPA receptors (Braithwaite et al, 2006). In addition, PTPN5 knock-out mice reveal a significant increase in NR1 and NR2B levels in synaptosomal membrane fractions from the hippocampus (Zhang et al, 2010).…”

PSD-95 stabilizes NMDA receptors by inducing the degradation of STEP 61

“…Interestingly, the expression level of GluN2B and the phosphorylation of GluN2B Y1472 were decreased. A reduction of GluN2B pY1472 may lead to diminished GluN2B levels at the PSD, because previous studies (19,27,30) have shown that phosphorylation of Y1472 in GluN2B increases the surface expression of GluN2B-containing NMDARs at the synapse.…”

“…The STEP family of protein tyrosine phosphatases includes both membrane-associated [striatal-enriched protein tyrosine phosphatase 61 (STEP 61 )] and cytosolic (STEP 46 ) variants that are generated by alternative splicing of a single gene (22)(23)(24). STEP 61 is present in the PSD of glutamatergic synapses (25,26) and has been shown to influence NMDAR-mediated synaptic currents and LTP in the hippocampus (17,(27)(28)(29). GluN2B is specifically phosphorylated by the Src family tyrosine kinase Fyn on tyrosine 1472, which is part of an endocytic motif (YEKL).…”

Glutamate system, amyloid β peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology

“…133 A role for striatal-enriched tyrosine phosphatase (STEP 61 ) has recently been linked to amyloid β-induced synaptic function since it increases the endocytosis of NMDA and AMPA receptors from the postsynaptic membrane. [133][134][135][136] The STEP 61 is enriched in synapses, suggesting that it has a specialized role in cell signalling. The levels of STEP 61 were reported to be increased in 2 mouse models of Alzheimer disease 133 and in humans 135 with Alzheimer disease.…”