Regulation of AMPA receptor extrasynaptic insertion by 4.1N, phosphorylation and palmitoylation

Abstract

The insertion of alpha–amino–3–hydroxy–5–methyl–4–isoxazolepropionic acid receptors (AMPARs) into the plasma membrane is a key step in synaptic delivery of AMPARs during the expression of synaptic plasticity. However, the molecular mechanisms regulating AMPAR insertion remain elusive. By directly visualizing individual insertion events of the AMPAR subunit GluR1, we demonstrate that Protein 4.1N is required for activity dependent GluR1 insertion. PKC phosphorylation of GluR1 S816 and S818 residues enhances 4.1N binding to GluR1, and facilitates GluR1 insertion. In addition, palmitoylation of GluR1 C811 residue modulates PKC phosphorylation and GluR1 insertion. Finally, disrupting 4.1N dependent GluR1 insertion decreases surface expression of GluR1 and the expression of long–term potentiation (LTP). Our study uncovers a novel mechanism that governs activity dependent GluR1 trafficking, reveals an interesting interplay between AMPAR palmitoylation and phosphorylation, and underscores the functional significance of the 4.1N protein in AMPAR trafficking and synaptic plasticity.

The Membrane Proximal Region of AMPA Receptors in Lateral Amygdala is Essential for Fear Memory Formation

“…By using a well-established and specific GluA1-MPR competing peptide (Boehm et al, 2006;Lin et al, 2009;Mitsushima et al, 2011), we show that GluA1-MPR has a key role in shortterm and long-term fear memory but not its retrieval. Furthermore, we show that microinjection of a GluA4-MPR protein fragment (Boehm et al, 2006;Correia et al, 2003;Gomes et al, 2007) impairs long-term but not short-term fear memory formation.…”

“…Previous studies have shown that GluA1-MPR and GluA4-MPR, but not GluA2-MPR, are needed for AMPAR insertion into synapse and neuronal membrane and for synaptic plasticity (Shi et al, 2001;Correia et al, 2003;Boehm et al, 2006;Gomes et al, 2007;Lin et al, 2009;Mitsushima et al, 2011). However, the role of AMPAR-MPR in LTM formation is not known.…”

“…GluA2-MPR region is not sufficient for the continuous delivery of GluA2 into the synapse and for protein interactions needed for its removal from the synapse (Shi et al, 2001;Lee et al, 2002;Boehm et al, 2006). GluA1 and GluA4 containing AMPAR trafficking is mediated by interaction of GluA1-MPR and GluA4-MPR with intracellular proteins, such as protein 4.1N and PKCγ (Shen et al, 2000;Coleman et al, 2003;Correia et al, 2003;Chen et al, 2005;Gomes et al, 2007;Lin et al, 2009). However, of note a recent study has shown that the MPR of GluA1 is not needed for protein trafficking or LTP in hippocampal CA1 (Granger et al, 2013).…”

A Possible Role for FRM-1, a C. elegans FERM Family Protein, in Embryonic Development

“…The band 4.1 proteins have also been shown to interact with and regulate the membrane localization of various receptors. For example, 4.1N interacts with D2 and D3 dopamine receptors (Binda et al, 2002) and AMPA receptors (Lin et al, 2009;Shen et al, 2000) and facilitates the cell surface expression of these receptors. Additionally, 4.1G and 4.1B are required for the proper localization and activation of parathyroid hormone receptors (Saito et al, 2005) and NMDA receptors (Hoy et al, 2009), respectively. A homology search identified 16 proteins containing the FERM domain in Caenorhabditis elegans (Van Furden et al, 2004).…”

Competition of Reactive Signals and Thiol Modifications of Proteins

“…However, more recently it has been realized that such modifications can also alter the activity of the protein more directly, so should be thought of as a cell signaling event, especially as they are reversible and again akin to phosphorylation. A key example of such an event is the increase in surface expression of AMPA receptors on the post-synaptic membranes of neurons during long-term potentiation, the major cellular model for the formation of memories [27]. Other important, and similar, modifications include SUMOylation [28] and ubiquitination [29].…”