Abstract
AbstractWe demonstrated previously that ethanol inhibition of NMDA receptor (NMDAR) function is accompanied by a reduction in tyrosine phosphorylation of Tyr^1472^ on the NR2B subunit, and this action of ethanol is attenuated by a broad spectrum tyrosine phosphatase inhibitor. Here we examined whether this ethanol inhibition of NMDAR activity was due to the actions of STriatal Enriched protein tyrosine Phosphatase (STEP) which has been shown to regulate NMDAR internalization by dephosphorylating Tyr^1472^ on the NR2B subunit. Using whole-cell recordings of pharmacologically isolated NMDAR-mediated excitatory post-synaptic currents (NMDA EPSCs) from hippocampal CA1 pyramidal neurons, we show that intracellular infusion of a substrate-trapping inactive form of STEP (TAT-STEP C/S) significantly blocks ethanol inhibition of NMDA EPSCs. Ethanol does not inhibit NMDA EPSCs or LTP in neurons from STEP knockout mice, but its effect is restored after acute intracellular delivery of wild type TAT-STEP, suggesting that STEP mediates ethanol inhibition of NMDAR function.
Highlights
The majority of excitatory synaptic transmission in the mammalian CNS is mediated by the neurotransmitter glutamate, which activates postsynaptic α-amino-3-hydroxy-5methyl-4-isoxalone propionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA) subtypes of ionotropic glutamate receptors[1]
Since the previous work with ethanol and the broad spectrum tyrosine phosphatase inhibitor bpV(phen) was determined using extracellular NMDA field EPSPs6, we first verified that bpV(phen) attenuates ethanol inhibition of NMDA receptor (NMDAR) function in individual pyramidal neurons from rat hippocampal slices
Given that the protein tyrosine phosphatase (PTP) inhibitor bpV(phen) prevented ethanol-induced inhibition of NMDAR function[6], we concluded that the inhibitory effects of ethanol on NMDARs were mediated by PTPs
Summary
The majority of excitatory synaptic transmission in the mammalian CNS is mediated by the neurotransmitter glutamate, which activates postsynaptic α-amino-3-hydroxy-5methyl-4-isoxalone propionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA) subtypes of ionotropic glutamate receptors[1]. Ethanol-induced inhibition of NMDAR function was prevented by bath application of the protein tyrosine phosphatase (PTP) inhibitor, bpV(phen) Based on these and other findings that showed ethanol reduced the tyrosine phosphorylation of NR2 subunits in the cortex[9], we proposed that ethanol inhibition of NMDAR activity is mediated by a PTP. The current hypothesis for STEP function is that it blocks the development of synaptic strengthening[23,24] Consistent with these findings, enhanced STEP activity is associated with dephosphorylation of the Tyr1472 residue on the NR2B subunit[25], a site that is dephosphorylated by ethanol[6]. NMDAR trafficking to synaptic membranes is increased after RNA interference of STEP23 Based on these data, we predicted that STEP mediates the inhibitory effects of ethanol on NMDARs in various brain regions, including the hippocampus. Our results show that STEP is responsible, at least in part, for the inhibitory effects of ethanol on hippocampal NMDAR activity
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