PICK1 is a calcium-sensor for NMDA-induced AMPA receptor trafficking

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 Ca(2+) 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 Ca(2+). PICK1 binds the AMPAR GluR2 subunit and is involved in AMPAR internalisation and LTD. We show that PICK1 is a Ca(2+)-binding protein, and that PICK1–GluR2 interactions are enhanced by the presence of 15 μM Ca(2+). Deletion of an N-terminal acidic domain in PICK1 reduces its ability to bind Ca(2+), and renders the GluR2–PICK1 interaction insensitive to Ca(2+). Overexpression of this Ca(2+)-insensitive mutant occludes NMDA-induced AMPAR internalisation in hippocampal neurons. This work reveals a novel postsynaptic Ca(2+)-binding protein that provides a direct mechanistic link between NMDAR-mediated Ca(2+) influx and AMPAR endocytosis

A calcineurin/AKAP complex is required for NMDA receptor–dependent long-term depression

AKAP79/150 is a protein scaffold thought to position specific kinases (PKA, PKC) and phosphastases (calcineurin) in appropriate synaptic domains so that their activities can regulate excitatory synaptic strength. Using a viral-mediated molecular replacement strategy in rat hippocampal slices, we found that AKAP is required for NMDA receptor-dependent LTD solely due to its interaction with calcineurin

Assembly of a β2-adrenergic receptor—GluR1 signalling complex for localized cAMP signalling

Central noradrenergic signalling mediates arousal and facilitates learning through unknown molecular mechanisms. Here, we show that the β2-adrenergic receptor (β2AR), the trimeric Gs protein, adenylyl cyclase, and PKA form a signalling complex with the AMPA-type glutamate receptor subunit GluR1, which is linked to the β2AR through stargazin and PSD-95 and their homologues. Only GluR1 associated with the β2AR is phosphorylated by PKA on β2AR stimulation. Peptides that interfere with the β2AR–GluR1 association prevent this phosphorylation of GluR1. This phosphorylation increases GluR1 surface expression at postsynaptic sites and amplitudes of EPSCs and mEPSCs in prefrontal cortex slices. Assembly of all proteins involved in the classic β2AR–cAMP cascade into a supramolecular signalling complex and thus allows highly localized and selective regulation of one of its major target proteins