The Regulation of AMPA Receptor Endocytosis by Dynamic Protein-Protein Interactions.

Jonathan G Hanley

doi:10.3389/fncel.2018.00362

Abstract

The precise regulation of AMPA receptor (AMPAR) trafficking in neurons is crucial for excitatory neurotransmission, synaptic plasticity and the consequent formation and modification of neural circuits during brain development and learning. Clathrin-mediated endocytosis (CME) is an essential trafficking event for the activity-dependent removal of AMPARs from the neuronal plasma membrane, resulting in a reduction in synaptic strength known as long-term depression (LTD). The regulated AMPAR endocytosis that underlies LTD is caused by specific modes of synaptic activity, most notably stimulation of NMDA receptors (NMDARs) and metabotropic glutamate receptors (mGluRs). Numerous proteins associate with AMPAR subunits, directly or indirectly, to control their trafficking, and therefore the regulation of these protein-protein interactions in response to NMDAR or mGluR signaling is a critical feature of synaptic plasticity. This article reviews the protein-protein interactions that are dynamically regulated during synaptic plasticity to modulate AMPAR endocytosis, focussing on AMPAR binding proteins and proteins that bind the core endocytic machinery. In addition, the mechanisms for the regulation of protein-protein interactions are considered, as well as the functional consequences of these dynamic interactions on AMPAR endocytosis.

Highlights

Since AMPAR subunit ubiquitination is regulated by ligand (AMPA) receptors (AMPARs) mediate the majority of fast synaptic excitation in the central nervous system, their regulation at the synapse is of fundamental importance to brain function
A major component of these forms of synaptic plasticity is the trafficking of AMPARs to or from synapses to increase or decrease the number of AMPARs localized at synapses, AMPAR Endocytosis and Protein Interactions and modulate the strength of synaptic transmission
GluA1 does not bind μ2 (Kastning et al, 2007), the recruitment of these Ca2+-permeable AMPARs to clathrin-coated pits (CCPs) might depend on their transmembrane AMPAR regulatory proteins (TARPs)-μ2 interactions, allowing for a subtly distinct mode of regulation compared to GluA2-containing AMPARs, which may be critical for specific kinds of plasticity that involve Ca2+

Summary

INTRODUCTION

Since AMPA receptors (AMPARs) mediate the majority of fast synaptic excitation in the central nervous system, their regulation at the synapse is of fundamental importance to brain function. The subject of this review article is AMPAR endocytosis, the consequence of which is the removal of receptors from the neuronal surface and from the synapse, leading to a decrease in synaptic strength (LTD) This process is essential for specific types of learning and memory systems (Griffiths et al, 2008; Connor and Wang, 2016; Migues et al, 2016). AMPAR subunits interact with a large (and still increasing) number of identified proteins, which facilitate and direct their trafficking between the synapse and the endosomal system These accessory proteins in turn interact with other binding partners that integrate them into fundamental cell biological systems such as the actin cytoskeleton or the core endocytic machinery. While the primary focus of this review is the protein-protein interactions involved in endocytosis per se, other interactions that precede endocytosis must be regulated for endocytosis to proceed, so are discussed here

DISSOCIATION FROM PSD SCAFFOLDS

THE ACTIN CYTOSKELETON

CONCLUDING REMARKS