NSF binds calcium to regulate its interaction with AMPA receptor subunit GluR2.
N-ethylmaleimide-sensitive fusion protein (NSF) is essential for numerous Ca(2+)-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 alpha-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 Ca(2+), 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 Ca(2+)-binding protein and that GluR2-NSF interactions are inhibited by the presence of 15 mumol/L Ca(2+). NSF Ca(2+)-binding is reciprocally inhibited by the presence of GluR2 C-terminus. Mutant of NSF that binds Ca(2+) with reduced affinity and binds GluR2 with reduced sensitivity to Ca(2+) was identied. In addition, the interaction of betaSNAP with PICK1 is sensitive to Ca(2+). This study demonstrates that the GluR2-NSF-betaSNAP-PICK1 complex is regulated directly by Ca(2+), allowing for the transduction of Ca(2+) signals into concerted alterations in protein-protein interactions to bring about changes in AMPAR trafficking during synaptic plasticity.
Hanley
Jonathan G
JG
MRC Centre for Synaptic Plasticity, Department of Anatomy, School of Medical Sciences, University of Bristol, University Walk, Bristol, UK. jon.hanley@bristol.ac.uk
D019943:Amino Acid Substitution; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D003598:Cytoskeletal Proteins; D052066:N-Ethylmaleimide-Sensitive Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins / Q000378:metabolism
D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins; C498298:PICK1 protein, rat; D018091:Receptors, AMPA; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins; D052066:N-Ethylmaleimide-Sensitive Proteins; C104722:glutamate receptor ionotropic, AMPA 2; D002118:Calcium