NSF binds calcium to regulate its interaction with AMPA receptor subunit GluR2

Abstract

N-ethylmaleimide-sensitive fusion protein (NSF) is essential for numerous Ca2+-triggered vesicle trafficking events. It functions as a molecular chaperone to regulate trafficking protein complexes such as the soluble NSF attachment protein (SNAP) receptor complex and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-protein interacting with C-kinase (PICK1) complex. AMPAR trafficking is fundamental to processes of synaptic plasticity, which may underlie learning and memory. Changes in synaptic strength brought about by AMPAR trafficking are triggered by a post-synaptic influx of Ca2+, which may have numerous molecular targets including PICK1. NSF binds AMPAR subunit glutamate receptor subunit 2 (GluR2) and functions to maintain receptors at the synapse. In this study, it was showed that NSF is a Ca2+-binding protein and that GluR2-NSF interactions are inhibited by the presence of 15 μmol/L Ca 2+. NSF Ca2+-binding is reciprocally inhibited by the presence of GluR2 C-terminus. Mutant of NSF that binds Ca2+ with reduced affinity and binds GluR2 with reduced sensitivity to Ca2+ was identied. In addition, the interaction of βSNAP with PICK1 is sensitive to Ca2+. This study demonstrates that the GluR2-NSF-βSNAP-PICK1 complex is regulated directly by Ca2+, allowing for the transduction of Ca2+ signals into concerted alterations in protein-protein interactions to bring about changes in AMPAR trafficking during synaptic plasticity. © 2007 The Authors.