Journal
EMBO JOURNAL
Volume 24, Issue 18, Pages 3266-3278Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.emboj.7600801
Keywords
AMPA; calcium; endocytosis; PICK1; synaptic plasticity
Categories
Funding
- MRC [G9629038] Funding Source: UKRI
- Medical Research Council [G9629038] Funding Source: researchfish
- Medical Research Council [G9629038(61600), G9629038] Funding Source: Medline
- Wellcome Trust [072005] Funding Source: Medline
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Regulation of AMPA receptor ( AMPAR) trafficking results in changes in receptor number at the postsynaptic membrane, and hence modifications in synaptic strength, which are proposed to underlie learning and memory. NMDA receptor-mediated postsynaptic Ca2+ influx enhances AMPAR internalisation, but the molecular mechanisms that trigger such trafficking are not well understood. We investigated whether AMPAR-associated protein - protein interactions known to regulate receptor surface expression may be directly regulated by Ca2+. PICK1 binds the AMPAR GluR2 subunit and is involved in AMPAR internalisation and LTD. We show that PICK1 is a Ca2+-binding protein, and that PICK1 - GluR2 interactions are enhanced by the presence of 15 mu M Ca2+. Deletion of an N-terminal acidic domain in PICK1 reduces its ability to bind Ca2+, and renders the GluR2 - PICK1 interaction insensitive to Ca2+. Overexpression of this Ca2+-insensitive mutant occludes NMDA-induced AMPAR internalisation in hippocampal neurons. This work reveals a novel postsynaptic Ca2+-binding protein that provides a direct mechanistic link between NMDAR-mediated Ca2+ influx and AMPAR endocytosis.
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