PICK1: A multi-talented modulator of AMPA receptor trafficking

doi:10.1016/j.pharmthera.2008.02.002

Pharmacology & Therapeutics

Volume 118, Issue 1, April 2008, Pages 152-160

https://doi.org/10.1016/j.pharmthera.2008.02.002 Get rights and content

Abstract

AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor trafficking is a fundamental mechanism for regulating synaptic strength, and hence may underlie cellular processes involved in learning and memory. PICK1 (protein interacting with C-kinase) is a PDZ and BAR domain-containing protein that has recently emerged as a key regulator of AMPA receptor traffic. Via the PDZ domain, PICK1 interacts directly with AMPA receptor subunits and is involved in the regulated removal of AMPA receptors from the synaptic plasma membrane. PICK1 has the ability to functionally interact with a number of cellular processes, including calcium signaling, actin polymerisation and phospholipid membrane architecture. In this review, I summarize recent findings that describe the importance of PICK1 in neurons and its specific molecular characteristics that enable it to regulate AMPA receptor trafficking.

Introduction

AMPARs (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors) mediate most fast excitatory synaptic transmission in the brain; therefore alterations in AMPAR number or function at the synapse brought about by regulated receptor trafficking can modulate synaptic strength. These processes have recently received much attention because they are proposed to underlie learning and memory. At a number of different synapses in the brain, LTD (long-term depression) involves endocytosis of AMPAR from the plasma membrane to reduce synaptic transmission, whereas LTP (long-term potentiation) involves insertion of additional AMPARs into the plasma membrane by exocytosis to enhance synaptic strength (Carroll et al., 2001, Malinow and Malenka, 2002, Bredt and Nicoll, 2003). Such trafficking events require a number of protein interactions with AMPAR subunits (Carroll et al., 2001, Malinow and Malenka, 2002, Song and Huganir, 2002, Bredt and Nicoll, 2003, Kim and Sheng, 2004, Palmer et al., 2005, Greger and Esteban, 2007). In addition to regulated trafficking during synaptic plasticity, AMPARs traffic constitutively under basal conditions, with continual rounds of endocytosis and reinsertion that allow for fast and effective control of synaptic receptor density (Nishimune et al., 1998, Luscher et al., 1999, Carroll et al., 2001, Malinow and Malenka, 2002, Bredt and Nicoll, 2003). The numerous proteins that bind to AMPAR subunits and regulate receptor trafficking are the subject of some excellent reviews (Carroll et al., 2001, Malinow and Malenka, 2002, Song and Huganir, 2002, Bredt and Nicoll, 2003, Kim and Sheng, 2004, Palmer et al., 2005, Greger and Esteban, 2007). Here, I will focus on PICK1 (protein interacting with C-kinase 1), which is a key regulator of AMPAR trafficking.

Section snippets

Role of PICK1 in AMPAR trafficking pathways

Originally isolated as a novel PKC (protein kinase C)-binding protein (Staudinger et al., 1995), PICK1 was subsequently shown to bind the C-terminal tail of AMPAR subunits GluR2 and GluR3 (Dev et al., 1999, Xia et al., 1999; Fig. 1). It is now well established that GluR2–PICK1 interactions are required for NMDA (N-Methyl d-aspartate)-induced removal of AMPAR from the synaptic plasma membrane during LTD in hippocampal neurons (Kim et al., 2001, Iwakura et al., 2001, Hanley and Henley, 2005,

Interactions with AMPAR subunits

The PDZ binding ligand (-SVKI) at the extreme C-terminus of GluR2 and GluR3 subunits of AMPARs can interact with PICK1, and also with GRIP1 (glutamate receptor interacting protein 1; Dong et al., 1997) and ABP (AMPAR binding protein; Srivastava et al., 1998), which is also known as GRIP2 (hereafter this family of proteins will be referred to collectively as ABP/GRIP). A popular model is that ABP/GRIP maintains AMPARs at the synaptic plasma membrane, and also at an undefined intracellular

PICK1 as a calcium sensor

Most forms of synaptic plasticity require intracellular Ca²⁺ signals to trigger appropriate regulated AMPAR trafficking events. NMDAR-dependent LTD and LTP both require influx of Ca²⁺ ions via NMDARs (Malinow and Malenka, 2002). Voltage-gated Ca²⁺ channels as well as IP3 receptor channels associated with intracellular Ca²⁺ stores provide the necessary Ca²⁺ signals for cerebellar LTD (Hartell, 2002). A number of Ca²⁺-dependent enzymes respond to these signals, particularly kinases and

PICK1 as a sensor of membrane curvature

Since PICK1 is involved in receptor trafficking, an important question is how does PICK1 associate with trafficking vesicles? Is it by interacting with the vesicle coat proteins, cargo (e.g. AMPARs), or does it associate with membranes independently of protein interactions? PICK1 contains a BAR domain that forms a large crescent-shaped structure in the dimeric protein. BAR domains are thought to function as sensors or stabilizers of membrane curvature (Peter et al., 2004, Itoh and De Camilli,

PICK1 as a regulator of the actin cytoskeleton

Actin depolymerisation is involved in AMPAR internalisation and LTD (Zhou et al., 2001, Okamoto et al., 2004), suggesting the existence of a mechanism to manipulate the actin cytoskeleton as part of AMPAR endocytosis. Actin dynamics are emerging as a crucial factor in providing a driving force for various stages of endocytosis in a wide range of cell types (Engqvist-Goldstein and Drubin, 2003, Merrifield, 2004, Kaksonen et al., 2006). The Arp2/3 complex is one of the major catalysts for

PICK1 as an allosteric protein

Certain multi-domain signaling proteins may be suppressed by adopting an inhibitory three-dimensional conformation via intramolecular interactions. Such proteins may be activated by binding of specific effector ligands that alter the 3D conformation (Lim, 2002). The PICK1 PDZ domain can bind to the BAR domain, resulting in a ‘closed’ conformation of the protein (Lu and Ziff, 2005, Rocca et al., 2008). This intramolecular interaction is disrupted upon binding of a PDZ ligand, such as GluR2

Concluding remarks

PICK1 has recently received much attention because of its role in synaptic plasticity, revealing a wealth of important information about its physiological function and molecular mechanisms. However, some important questions about the function of PICK1 in AMPAR trafficking remain unanswered. For example, how does PICK1 bring about changes in the synaptic AMPAR population with respect to GluR2 content? The elaborate endosomal sorting events that may be involved in this process will no doubt be

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Associate Editor: K. W. RochePICK1: A multi-talented modulator of AMPA receptor trafficking

Abstract

Introduction

Section snippets

Role of PICK1 in AMPAR trafficking pathways

Interactions with AMPAR subunits

PICK1 as a calcium sensor

PICK1 as a sensor of membrane curvature

PICK1 as a regulator of the actin cytoskeleton

PICK1 as an allosteric protein

Concluding remarks

Neuron

Curr Opin Neurobiol

Neuron

Neuropharmacology

Neuron

Curr Opin Neurobiol

Neuron

Neuron

Neuron

Biochim Biophys Acta

Dev Cell

J Biol Chem

Neuron

Neuron

Curr Opin Struck Biol

Neuron

Neuron

J Biol Chem

Trends Cell Biol

Neuron

Neuron

Neuron

J Biol Chem

Trends Neurosci

Neuron

Mol Cell Neurosci

Neuron

Neuron

Biochem Biophys Res Commun

Neuron

Neuron

Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression

Nat Neurosci

Role of AMPA receptor endocytosis in synaptic plasticity

Nat Rev Neurosci

Associate Editor: K. W. Roche
PICK1: A multi-talented modulator of AMPA receptor trafficking