AMPAR exocytosis through NO modulation of PICK1

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.