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

Abstract

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 μM 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

The Ampakine CX546 Restores the Prepulse Inhibition and Latent Inhibition Deficits in mGluR5-Deficient Mice

“…It is possible that positive AMPAR modulators could activate NMDAR as there is a link of these two receptors (Hanley and Henley, 2005) and lead to improved behavior in mGluR5 À/À animals. Indeed, we observed that both positive AMPAR modulatorsFaniracetam and CX546Fhad positive effects on impaired PPI of mGluR5 mutant mice but with different efficacies.…”

“…Indeed, using electrophysiological measurements, we found that CA1 neurons from mGluR5 À/À mice showed a complete loss of the NMDARmediated component of long-term potentiation (LTP NMDA ), but an unchanged LTP of AMPAR-mediated component (LTP AMPA ) (Jia et al, 1998). We hypothesized here that membrane depolarization via AMPAR facilitation could activate NMDAR complex as there is a link between these two receptors (Hanley and Henley, 2005) and overcome behavioral deficits of mGluR5 À/À animals. AMPAR are heteromeric complexes composed of four subunits (GluR1, GluR2, GluR3, and GluR4), each of which has a binding pocket for the transmitter glutamate and can be expressed as flip or flop splice variant, which is regulated regionally (Black, 2005).…”

PICK1 promotes caveolin-dependent degradation of TGF-β type I receptor

“…As a peripheral protein, PICK1 has been reported to interact with a series of membrane proteins including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) [13][14][15][16], acid-sensing ion channel (ASICs) [17] and ErbB2/Her-2 [18]. In most of the cases, PICK1 acts as a critical regulator of membrane receptors' subcellular trafficking to modulate neural processes such as learning and memory [19,20].…”

Presynaptic PICK1 facilitates trafficking of AMPA-receptors between active zone and synaptic vesicle pool

“…At the postsynaptic site, both PICK1 and NSF contribute to regulating GluA2 insertion and retraction from the plasma membrane in a calcium dependent manner (Hanley and Henley, 2005). Our data suggest that PICK1 and NSF may play a similar role in the presynaptic terminal, where overexpression of PICK1, as well as expression of pep2m, reduces the labeling intensity of GluA2 at plasma membrane and cytoplasmic sites.…”

“…The interaction between PICK1 and GluA2 is involved in the removal of GluA2 from the plasma membrane during long-term depression (LTD) in the hippocampus (Iwakura et al, 2001;Kim et al, 2001;Hanley and Henley, 2005) and the cerebellum (Xia et al, 2000;Steinberg et al, 2006;Hanley, 2008;Terashima et al, 2008).…”