AMPAR exocytosis through NO modulation of PICK1

doi:10.1016/j.neuropharm.2007.04.005

Neuropharmacology

Volume 53, Issue 1, July 2007, Pages 92-100

https://doi.org/10.1016/j.neuropharm.2007.04.005 Get rights and content

Abstract

The activation of NMDA receptors (NMDARs) triggers long-term changes in AMPA receptor-mediated synaptic transmission in the CNS. These long-lasting changes occur via the addition or removal of AMPA receptors (AMPARs) at the synaptic membrane and are mediated by a number of regulatory proteins including the GluR2 AMPAR-interacting proteins n-ethylmaleimide sensitive factor (NSF) and Protein Interacting with C Kinase (PICK1). We have shown that the potent activation of NMDARs drives unclustering of PICK1 and PICK1-GluR2 dissociation in dendrites resulting in increased surface delivery of AMPARs. Here we show that the dispersal of PICK1 is mediated by the actions of NSF. We find that elevated NMDAR signaling leads to the S-nitrosylation of NSF and increased NSF-GluR2 association. Both NMDAR-dependent unclustering of PICK1 and the delivery of surface AMPARs are dependent on release of nitric oxide (NO). Our data suggest that NMDAR activation can drive the surface delivery of AMPARs from a pool of intracellular AMPARs retained by PICK1 through the NO-dependent modification of NSF.

Introduction

NMDA receptor-induced increases in AMPAR trafficking to the synaptic surface mediates changes in synaptic efficacy in a number of brain regions (Shi et al., 1999, Sun et al., 2005, Frenkel et al., 2006). While this process has been linked to the regulated insertion of GluR1-containing AMPARs, subsequent insertion of GluR2-containing receptors is also critical to maintaining synaptic potentiation (Hayashi et al., 2000, Passafaro et al., 2001, Plant et al., 2006). However, evidence for a role or mechanism of regulated GluR2-containing AMPARs insertion is limited. We have previously found that elevated NMDAR activation unclusters dendritic PICK1 and results in the release of GluR2-containing AMPARs (GluR2-AMPARs) to the membrane surface (Sossa et al., 2006). This PICK1-dependent increase in surface AMPARs suggests that GluR2 localization with and retention by PICK1 in intracellular pools serves as a site of regulation for receptor-induced changes in synaptic transmission. To provide additional insight into the mechanisms of such NMDAR-induced plasticity, further examination of the mechanisms that regulate PICK1 clustering is required.

The process of modulating GluR2-AMPAR levels at synapses is regulated by a number of AMPA receptor interacting proteins (Braithwaite et al., 2000, Kim and Sheng, 2004), one of which is N-ethylmaleimide sensitive factor (NSF). NSF chaperones GluR2-AMPARs to the membrane surface and disassembles PICK1 from GluR2-AMPARs (Hanley et al., 2002), perhaps freeing pools of intracellularly anchored AMPARs to return to the membrane surface. Activation of NSF by nitric oxide (NO)-dependent S-nitrosylation increases the binding of NSF to GluR2 and enhances the surface expression of AMPARs (Huang et al., 2005). We have, therefore, investigated whether the PICK1-dependent delivery of AMPARs following NMDAR activation is mediated by NSF and its modification by NO.

We find that dendritic PICK1 unclustering and the subsequent delivery of AMPARs to the membrane surface occurs via NMDAR-mediated S-nitrosylation of NSF. NMDAR stimulation increases NO production and S-nitrosylation of NSF. Consistent with the possibility that S-nitrosylation increases NSF function, we find that NMDA/low Mg²⁺ treatment increases NSF-GluR2 association and surface AMPAR levels. NO donors mimic the NMDA/low Mg²⁺-induced decrease in dendritic PICK1 levels, a result blocked by NO scavengers. We show that the NMDA/low Mg²⁺-induced loss in PICK1 labeling is an NO-dependent process, which leads to enhanced NSF function and subsequent increase in surface AMPAR expression.

Section snippets

Reagents and antibodies

Antibodies: PICK1 (Affinity Bioreagents; rabbit polyclonal 1:1000 for IF), GluR2 (Chemicon International, Inc., Temecula, CA; N-terminal mouse monoclonal 5 μg for IP and 1:100 for IF), NSF antibody (BD Transduction Laboratories, San Jose, CA; mouse monoclonal 1:1000 for Western blotting).

Primary hippocampal cultures

Cultured hippocampal neurons were prepared as previously described (Sossa et al., 2006). Hippocampi were dissected out of P0 rat pups, dissociated with papain, and plated on poly-d-lysine coated coverslips. For

NMDA/low Mg²⁺-dependent unclustering of dendritic PICK1 requires NSF activity

We have previously reported that brief, potent pharmacological activation of NMDARs (20 μM, 1 min in low Mg²⁺ ACSF) results in the unclustering of dendritic PICK1 (Sossa et al., 2006). The disassembly of PICK1 from the GluR2 AMPAR subunit has been shown to be enhanced by the ATPase activity of NSF when bound to soluble NSF associated protein (Hanley et al., 2002), resulting in enhanced surface delivery of AMPARs. To investigate whether NMDA/low Mg²⁺ treatment may uncluster PICK1 through

Discussion

This study shows that NO can affect the plasma membrane expression of a population of receptors regulated by PICK1. Our data further elucidates a mechanism underlying the surface delivery of AMPARs following NMDAR activation. NMDAR stimulation enhances nitric oxide levels in hippocampal neurons and induces an increase in the S-nitrosylation of NSF. Consistent with work by Huang et al. (2005), this modification of NSF is accompanied by an increase in the binding of NSF to GluR2. We now find that

Acknowledgements

This work was supported by NIH/NINDS NS 049661 and the Whitehall Foundation. KGS was supported by NIH Training Grant 5T32NS007439.

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AMPAR exocytosis through NO modulation of PICK1

Abstract

Introduction

Section snippets

Reagents and antibodies

Primary hippocampal cultures

NMDA/low Mg2+-dependent unclustering of dendritic PICK1 requires NSF activity

Discussion

Acknowledgements

Neuropharmacology

J. Biol. Chem.

Neuron

Neuron

Neuron

Neuron

Trends Neurosci.

Mol. Cell. Neurosci.

Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum

Proc. Natl. Acad. Sci. U.S.A.

Nitric-oxide-guanylyl-cyclase-dependent and -independent components of multiple forms of long-term synaptic depression

Hippocampus

Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction

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NMDA/low Mg²⁺-dependent unclustering of dendritic PICK1 requires NSF activity