The Tyrosine Phosphatase STEP Mediates AMPA Receptor Endocytosis after Metabotropic Glutamate Receptor Stimulation

Abstract

Although it is well established that AMPA receptor (AMPAR) trafficking is a central event in several forms of synaptic plasticity, the mechanisms that regulate the surface expression of AMPARs are poorly understood. Previous work has shown that striatal-enriched protein tyrosine phosphatase (STEP) mediates NMDAR endocytosis. This protein tyrosine phosphatase is enriched in the synapses of the striatum, hippocampus, cerebral cortex, and other brain regions. In the present investigation, we have explored whether STEP also regulates AMPAR internalization. We found that (RS)-3,5-dihydroxyphenylglycine (DHPG) stimulation triggered a dose-dependent increase in STEP translation in hippocampal slices and synaptoneurosomes, a process that requires stimulation of mGluR5 (metabotropic glutamate receptor 5) and activation of mitogen-activated protein kinases and phosphoinositide-3 kinase pathways. DHPGinduced AMPAR internalization and tyrosine dephosphorylation of GluR2 (glutamate receptor 2) was blocked by a substrate-trapping TAT-STEP [C/S] protein in hippocampal slices and cultures. Moreover, DHPG-triggered AMPAR internalization was abolished in STEP knock-out mice and restored after replacement of wild-type STEP. These results suggest a role for STEP in the regulation of AMPAR trafficking.

Cocaine-Induced Changes of Synaptic Transmission in the Striatum are Modulated by Adenosine A2A Receptors and Involve the Tyrosine Phosphatase STEP

“…STEP mediates AMPA and NMDA receptor subunit endocytosis through tyrosine dephosphorylation of their subunits (Zhang et al, 2008;Zhang et al, 2010Zhang et al, , 2011Kurup et al, 2010). In agreement with a recent study (Sun et al, 2013), we found that cocaine reduced the phosphorylation level of the NMDAR subunit GluN2B, an effect prevented by ZM241385 and absent in stA 2A RKO.…”

“…STEP is highly enriched in the striatum and regulates AMPA receptor internalization (Zhang et al, 2008). The two major isoforms, STEP 46 and STEP 61 , are revealed by western blot analysis in striatal slices, and cocaine (10 mM, 10 min) induced an increase in protein levels of both isoforms ( Figure 4b).…”

“…Active STEP dephosphorylates tyrosine residues on its substrates causing their inactivation and, in the case of glutamate receptors, promoting their internalization from synaptosomal surface membranes (Zhang et al, 2008;Zhang et al, 2010Zhang et al, , 2011. Substrates of STEP include the GluN2B subunit of the NMDA receptor.…”

Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase

“…Moreover, STEP reduces NMDAR activity, negatively regulates LTP, and is required for internalization of both NMDARs and AMPARs from neuronal surfaces (31,32). Based on these results, we hypothesized that STEP may mediate the inhibitory effects of ethanol on NMDAR activity in the brain.…”

Cocaine and Amphetamine Induce Overlapping but Distinct Patterns of AMPAR Plasticity in Nucleus Accumbens Medium Spiny Neurons

“…Within striatal regions, Arc protein expression is robustly induced following re-exposure to cocaine-paired stimuli and modulates extinction of drugseeking behavior (Hearing et al, 2011;Hearing et al, 2008). In addition, mGluR activation has been shown to induce rapid translation of striatal-enriched protein tyrosine phosphatase (STEP), which also downregulates AMPAR surface expression and may actively maintain endocytosis rates (Luscher and Huber, 2010;Zhang et al, 2008). Acute exposure to both amphetamine and cocaine alters phosphorylation of STEP in striatal regions and inactivation of STEP prevents cocaineinduced reductions in AMPAR-mediated currents in MSNs (Chiodi et al, 2014;Sun et al, 2007;Tashev et al, 2009;Valjent et al, 2005).…”