The Postsynaptic Density

The postsynaptic density is a dense, submembranous filamentous structure beneath the postsynaptic membrane. It is a disklike structure that may or may not display perforations. The intimacy of its association with the postsynaptic membrane is reflective of the distribution of some proteins, which are shared between the PSD and postsynaptic membrane, e.g., receptors, ion channels, and adhesion proteins. The PSD displays a complex array of proteins, which are arranged in a hierarchical manner: (1) receptors, ion channels, and adhesion proteins shared with the postsynaptic membrane; (2) scaffold proteins connecting the receptors to each other, to other membrane components, and to the actin cytoskeleton; and (3) the actin-based cytoskeleton, itself. The core structure of the PSD appears to be the scaffold protein postsynaptic density-95 (PSD-95). Another key component of the PSD is the enzyme Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), which is capable of autophosphorylation and, thus, has been implicated in long-term processes. The PSD has been shown to undergo morphological alterations in various parameters with behavioral, hormonal, and electrophysiological inputs. The PSD is important in signal transduction events at the synapse and may be involved in information storage.

Authors and Affiliations

1. Department of Anatomy and Cell Biology (MC 512), University of Illinois at Chicago College of Medicine, 808 South Wood Street, 60612, Chicago, IL, USA

   Prof. Rochelle S. Cohen

Corresponding author

Correspondence to Rochelle S. Cohen .

Editors and Affiliations

1. Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY, USA

   Donald W. Pfaff

Actin

A cytoskeletal protein 6 nm in diameter and found in both monomeric (G-actin) and filamentous (F-actin) forms. It is found in muscle and non-muscle cells.

Adenosine Triphosphate (ATP)

A nucleotide produced by phosphorylation and cellular respiration used as an energy source and as a substrate in signal transduction pathways by kinases and adenylate cyclase. Adenylate cyclase uses ATP to produce cyclic AMP a second messenger molecule.

Adhesion Proteins

Proteins involved in the binding of cells to each other usually consisting of an intracellular domain that may interact with the cytoskeleton, a transmembrane domain and an extracellular domain.

AMPA Receptor Binding Protein (ABP)

An AMPA receptor binding protein that interacts with glutamate receptor 2/3 (GluR2/3) is homologous to glutamate receptor-interacting protein (GRIP) and is localized to the postsynaptic density. It contains seven PDZ domains and may be involved in AMPA receptor regulation and localization.

Ca²⁺/Calmodulin-Dependent Protein Kinase II (CaMKII)

An enzyme with an ability to phosphorylate its target substrates one of which is itself in a process called autophosphorylation.

Chemical Long-Term Potentiation (cLTP)

Induction of potentiation by chemical means such as with application of the adenyl cyclase activator forskolin and the phosphodiesterase inhibitor rolipram.

Complex Environment (EC)

A large cage filled with toys for example.

Electron Microscopic Tomography

An advanced electron microscopic technique whereby computed slices of tissues that are thinner than those prepared using conventional thin sectioning techniques reveal relationships of structures to each other.

Excitatory Postsynaptic Currents (EPSCs)

The flow of ions into a postsynaptic cell due to the opening of ligand-sensitive channels. It is a synaptic current that increases the probability of an action potential firing and is mediated by an increase in Na⁺ or Ca²⁺ conductance or a decrease in K⁺ conductance.

Gamma Aminobutyric Acid (A) Receptor-Associated Protein (GABARAP)

A member of a small family of ubiquitin homologous proteins. It clusters neurotransmitter receptors by mediating interaction with the cytoskeleton.

Gamma Aminobutyric Acid (GABA)

An inhibitory neurotransmitter. Inhibitory transmitters are likely to block the events that cause an action potential in the responding neuron.

Gamma Aminobutyric Acid (GABA) Receptors (GABARs)

GABAA receptors are ligand-gated chloride ion channels and GABAB receptors are G-protein-coupled receptors.

Glutamate Receptor-Interacting Protein (GRIP)

A scaffold protein containing PDZ domains. It is an AMPA receptor binding protein and appears to be involved in the targeting of AMPA receptors.

G-Protein-Coupled Inward Rectifying K⁺ (GIRK) Channels

A family of inward rectifier potassium ion channels that open via a signal transduction cascade. Pertussis toxin-sensitive G-protein-coupled receptors lead the cascade releasing activated G protein βγ-subunits (G_βγ) from inactive G protein complexes (Gαβγ). The G_βγ protein then interacts with G-protein-coupled inward rectifying K⁺ (GIRK) channels, which then open and become permeable to potassium ion. Hyperpolarization of the cell results. The channels regulate slow postsynaptic inhibitory signaling and hormone secretion.

Green Fluorescent Protein (GFP)

A protein derived from the jellyfish Aequorea victoria. The jellyfish contains a photoprotein called aequorin, which releases blue light when bound to calcium. The blue light is absorbed by green fluorescent protein, which then gives off a green light. The green fluorescent protein gene may be joined to a gene for a protein of interest, and when the protein is translated, it will have green fluorescent protein associated with it. Following excitation with blue light, it will exhibit green fluorescence.

Guanosine Triphosphate (GTP)

A purine nucleotide important in signal transduction particularly with G proteins.

Guanylate Kinase-Associated Protein (GKAP)

A protein that links Shank to the PSD-95 protein complex including NMDA-type glutamate receptors. It is a synaptic protein that binds directly to the guanylate kinase-like (GK) domain of the four members of the PSD-95 family, and it appears to be a major component of the postsynaptic density. GKAP may link ion channel/PSD-95 clusters to the subsynaptic cytoskeleton or downstream signal transduction cascades. It undergoes activity-dependent ubiquitination and degradation, thereby playing a role in activity-dependent synaptic remodeling via the ubiquitin-proteosome system.

Homer

A postsynaptic scaffolding protein involved in maintenance and activity-induced synaptic plasticity.

Impoverished or Isolated Conditions (IC)

A standard laboratory cage.

Inositol Triphosphate (IP3) and Inositol Triphosphate Receptor (IP3R)

IP3 is involved in signal transduction. IP3 and diacylglycerol are generated when an extracellular regulatory molecule binds to a membrane receptor that activates a G protein. The alpha subunit of the G protein subsequently activates the enzyme phospholipase C which cleaves off IP3 from a membrane phospholipid with diacylglycerol remaining in the membrane. Specifically, IP3 binds to its receptor IP3R on the membrane of the rough endoplasmic reticulum and sarcoplasmic reticulum of muscle and opens a calcium channel, resulting in the release of calcium into the cytoplasm and sarcoplasm of muscle, respectively. The calcium then activates various cellular processes.

Ionotropic Glutamate Receptors (iGLURs)

Heteromeric ligand-gated ion channels which open in response to glutamate and play a role in the mediation of excitatory synaptic transmission. They display four hydrophobic regions within its central portion.

Latrunculin

A toxin derived from sponges which binds to actin and prevents its polymerization.

Long-Term Depression (LTD)

A persistent reduction in synaptic efficacy resulting from either high- or low-frequency stimulation.

Long-Term Potentiation (LTP)

Alterations in synaptic strength that persists in brain slices and in intact animals when high-frequency tetani is applied to the perforant pathway of the hippocampus a brain region involved in memory storage.

Membrane-Associated Guanylate Kinase-Like Proteins (MAGUK) Family

A family of scaffolding proteins which are involved in the regulation and formation of cell junctions.

Metabotropic Glutamate Receptors (mGLURs)

Types of glutamate receptors which are members of the G-protein-coupled receptors. They have seven transmembrane domains, which span the cell membrane. They do not function as ion channels like ionotropic glutamate receptors but, rather, activate biochemical cascades which, in turn, lead to the modification of other proteins and, ultimately, processes.

Microtubule-Associated Proteins (MAPs)

Accessory proteins associated with microtubules that are involved in assembly and stabilization of microtubules and binding to other microtubules or other filaments or cell organelles.

Nanometer (nm)

One billionth (10⁻⁹) of a meter.

N-Cadherin

A molecule meaning “calcium-dependent adhesion.” It is calcium dependent and plays a role in cell adhesion.

N-Ethylmaleimide-Sensitive Factor (NSF)

A scaffold protein which participates in AMPA receptor trafficking.

Neuroligins

Adhesion molecules involved in trans-synaptic signaling.

N-Methyl-d-Aspartic Acid (NMDA) Receptor

A glutamate receptor that regulates a channel permeable to Ca²⁺ K⁺, and Na⁺.

Palmitoylation

A posttranslational lipid modification of neuronal proteins.

PDZ Domain

A structural domain of 80–90 amino acids. PDZ is an acronym for the first letters of the three proteins: PSD-95; Drosophila disc large tumor suppressor; and zona occludens-1 protein.

Postsynaptic Density (PSD)

Dense area behind the postsynaptic membrane containing receptors ion channels, scaffolding proteins, and cytoskeletal proteins.

Postsynaptic Density Protein (PSD-95)

A molecule displaying a sequence of three repeated 90 residue domains called PDZ (PSD-95; Drosophila disc large tumor suppressor; and zona occludens-1 protein) domains an SH3 domain, and a guanylate kinase-like (GK) domain, which acts as a protein binding domain. It is a member of the core scaffold complex of excitatory synapses.

Protein Interacting with Kinase C (PICK)

Scaffold proteins displaying a string of PDZ domains. PICK1 interacts with glutamate receptor subunits and participates in AMPA receptor trafficking.

Protein Kinase C α (PKCα)

A family of serine- and threonine-specific protein kinases that can be activated by calcium and diacylglycerol. It is involved in AMPA receptor trafficking.

Proteonomic Profiling

Proteomics subject to quantitative analysis revealing differences in protein expression across samples.

Proteonomics

The study of an organism’s complete array of proteins encompassing those modifications made to specific sets of proteins, including phosphorylation, ubiquitination, and others. The word proteome, itself, is derived from proteins and genome. Various techniques contribute to the study of proteonomics, including those which ascertain protein-protein interactions, such as protein microarrays and mass spectrometry.

Pseudophosphorylation

A process whereby a mutated form of calcium/calmodulin-dependent protein kinase II (CaMKII) maintains the enzyme in its active state independent of Ca²⁺/calmodulin binding. It is a functional “mimicry” of phosphorylation.

Shank

A family of scaffold proteins containing many sites for protein-protein interactions, located at postsynaptic sites of brain excitatory synapses.

Small-Conductance Ca²⁺-Activated K⁺ (SK) Channels

A subfamily of K⁺-activated Ca²⁺ channels. Activated by an increase in intracellular Ca²⁺ concentration they permit K⁺ movement across the cell membrane. When activated, the firing frequency of action potentials is limited and the resultant hyperpolarization decreases the firing frequency of action potentials in several neurons. It is important in regulating after hyperpolarization and also plays a role in the regulation of dendritic excitability, synaptic transmission, and synaptic plasticity.

Social Environment (SC)

A standard laboratory cage containing one other rat.

Stargazin

A transmembrane protein specific to brain, its cytoplasmic tail influences AMPA receptor trafficking, i.e., clustering and regulation of AMPA receptors, and the domain projecting into the extracellular space regulates channel gating.

Subcellular Fractionation

A method for enriching cell fractions. First differential centrifugation separates nuclear, cytoplasmic, and membrane components based on the size and density of particular organelles. Following differential centrifugation, enrichment of other organelles and/or membranes is achieved by density gradient centrifugation, whereby a continuous or stepped gradient of sucrose or cesium chloride is formed in a centrifuge tube. The relevant sample is placed on top of the gradient, and following further centrifugation at high relative centrifugal forces (g-force), particular organelles will settle at the position in the gradient at which their density corresponds to that of the surrounding sucrose or cesium chloride.

Synapse-Associated Protein 90/Postsynaptic Density-95-Associated Protein (SAPAP)

A protein concentrated in the postsynaptic density and binds to the guanylate cyclase domain of PSD-95.

Synapses

Sites of contacts between nerve cells. Chemical neurotransmission takes place at these sites.

Synaptosomal Membrane Fraction

A fraction of membranes enriched in membranes from the presynaptic and postsynaptic terminals. They are obtained after lysing the synaptosome the pinched-off nerve ending, with water or dilute buffer, and enriched upon density gradient centrifugation.

Synaptosomes

Nerve endings pinched off from axons. They are formed during homogenization of brain tissue.

SynGAP

A Ras-GTPase activating protein that interacts with the PDZ domains of PSD-95 and synapse-associated protein (SAP) 102. It associates with NMDA-type glutamate receptor.

Transmembrane Receptor AMPA Regulating Proteins (TARPs)

Proteins involved in the trafficking and regulation of AMPA receptors. Stargazin is a member of the TARP family.

α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid (AMPA) Receptor

A glutamate receptor that regulates a channel permeable to Na⁺ and K⁺.

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