Cell Biology of the Synapse

Abstract

Synapses are the sites of contact between nerve cells. Synapses convert electrical signals into chemical information, which is conveyed between neurons at this site. The synapse consists of both pre- and postsynaptic elements. The salient feature of the presynaptic terminal is a cohort of electron-lucent synaptic vesicles, which contain non-peptide neurotransmitters; dense-cored vesicles may also be present and contain catecholamines and neuropeptides. Upon release from the vesicle, these molecules bind to specific receptors on the postsynaptic membrane. The release of the vesicular contents, itself, depends upon an array of proteins present in the vesicular and presynaptic membranes. Among these are the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Beneath the postsynaptic membrane is a dense filamentous array termed the postsynaptic density (PSD). 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. A 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 is important in signal transduction events at the synapse and may be involved in information storage. Receptive surfaces include those on dendrites, dendritic spines, the cell body, and other axon terminals. Dendritic spines contain the cytoskeletal protein actin, which may be involved in spine structural and functional alterations. Some synapses have structural characteristics that are specialized, and these include neuromuscular junctions, ribbon synapses, and squid giant synapses. Whereas all synapses conform to a basic structural plan and transmit information with a great degree of fidelity, synapses also possess the ability to modify the manner in which incoming signals are received, modified, and transmitted, a property termed plasticity. Plasticity depends on the molecular variability present at different synapses and activity-dependent synaptic plasticity, which, in turn, may depend upon local regulation of protein translation.

Glossary

Actin

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

Actin-Associated Proteins

Accessory proteins involved in the polymerization and depolymerization of actin, branching of actin filaments, and other actin-dependent processes.

Adhesion Molecules

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.

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)

An agonist for the AMPA receptor (AMPAR).

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) Receptor

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

ARC

An immediate early gene product activity-regulated cytoskeleton protein, which promotes synaptic connectivity.

Autism Spectrum Disorders (ASDs)

A group of disorders with similar characteristics, including autistic disorder, Asperger’s syndrome, and atypical autism.

Axoaxonic Synapse

A synapse composed of an axon terminal contacting another axon terminal.

Axodendritic Synapse

A synapse composed of a presynaptic terminal in contact with a dendrite.

Axosomatic Synapse

A synapse composed of a presynaptic terminal in contact with the cell body. The cell body is also called the soma or perikaryon.

Axospinous Synapse

A synapse composed of a presynaptic terminal in contact with small protuberances on dendrites called dendritic spines.

Brain-Derived Neurotrophic Factor (BDNF)

A protein which functions to support neuronal survival and growth and differentiation of neurons and synapses.

Cadherins

Proteins involved in cell adhesion through homophilic binding and dependent on calcium (named for calcium-dependent adhesion). It is also involved in cell signaling by binding to other proteins or via protease-mediated cleavage.

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.

Ca²⁺/Calmodulin-Dependent Serine Protein Kinase (CASK)

A member of the membrane-associated guanylate kinase-like proteins (MAGUK) family of scaffolding proteins that binds presynaptic cytosolic proteins that are involved in neurosecretion.

Cytoplasmic Fragile-X Mental Retardation Interacting Protein (CYFIP)

A binding partner of fragile X mental retardation protein. It binds the translation initiation factor eIF4E forming a CYFIP-eIF4E complex. It appears to be involved in the translational repression activity of fragile X mental retardation protein.

Cytoplasmic Polyadenylation Element-Binding Protein (CPEB)

An RNA-binding protein promoting the elongation of the polyadenine tail of the messenger RNA. It usually activates the target RNA for translation but can also serve as a repressor depending on the state of phosphorylation.

Dihydropyridine Receptors

L-type voltage-dependent calcium channels in the T-tubules of skeletal muscle, in close proximity to calcium release channels, i.e., ryanodine receptors in the sarcoplasmic reticulum. When activated by depolarization, the dihydropyridine receptors, in turn, activate the calcium release channels to release calcium from the sarcoplasmic reticulum.

IgG Superfamily

A group of cell surface and soluble proteins involved in recognition, binding, and adhesion of cells.

Electron Tomographic Microscopy

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.

Eukaryotic Initiation Factor 4E (EIF4E)-Binding Proteins

A translation initiation factor in eukaryotes. It binds the first nucleotide on the 5′ end of an RNA molecule, i.e., the “cap,” a 7-methylguanosine, eventually bringing it to the ribosome.

Eukaryotic Initiation Factors (eIFs)

Proteins involved in the initiation phase of translation in eukaryotic cells.

Exocytosis

A mechanism by which synaptic vesicles appear to collapse into the plasma membrane of the presynaptic terminal during the release of neurotransmitter.

FMRF(phe-met-arg-phe-NH₂) Amide

A neuroactive peptide derived from mollusks capable of inducing a fast excitatory depolarizing response based on its direct activation of amiloride-sensitive sodium channels.

Fragile X Syndrome

The most prevalent heritable form of mental retardation resulting from a change in the FMR1 gene, the protein (FMRP [fragile X mental retardation protein]) of which is required for normal neural development. It is associated with an expansion of the CGG trinucleotide gene sequence on the X chromosome.

Gamma-Aminobutyric Acid (GABA)

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

G proteins

Proteins which bind the guanine nucleotides GDP and GTP. The “large” G proteins are composed of three different subunits (alpha, beta, and gamma) and are, therefore, heterotrimers. They are associated at the inner surface of the plasma membrane with transmembrane receptors called G-protein-coupled receptors (GPCRs). The “small” G proteins are members of the Ras superfamily of GTPases. They are homologous to the aforementioned alpha subunit and are monomeric. Activation of G proteins sets in motion signal transduction cascades.

Guanosine Triphosphate (GTP)

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

Guanylate Kinase-Associated Proteins (GKAP)

A synaptic protein binding directly to the guanylate kinase-like domain of the four members of the mammalian PSD-95 family. GKAP is an important constituent of the postsynaptic density.

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.

Microtubule

A cytoskeletal element 25 nm in diameter formed from tubulin subunits and found in axons and dendrites.

“Kiss and Run” Fusion

A mechanism by which there appears to be an incomplete and transient fusion of the vesicle membrane and plasma membrane, creating a pore-like opening through which the contents are released.

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 persist 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.

Mammalian Target of Rapamycin (mTOR)

A protein belonging to the phosphoinositol 3-kinase-related kinase protein family. It is a serine/threonine protein kinase involved in the regulation of cell growth, proliferation, motility, survival, protein synthesis, and transcription.

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

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

Messenger Ribonucleoproteins (mRNPs)

A complex of messenger ribonucleic acid (mRNA) and protein. Within an RNP particle, a transcript is bound by a various sets of proteins, which change upon cotranscriptional and posttranscriptional events related to the particular transcript.

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.

Neurexins

Adhesion molecules involved in transsynaptic signaling and which bind to transmembrane proteins of postsynaptic membranes, the neuroligins, to hold the synapse in register.

Neuroligins

Adhesion molecules involved in transsynaptic signaling.

N-methyl-d-aspartic acid (NMDA)

An amino acid derivative which mimics the amino acid glutamate at the NDMA receptor (NMDAR), but has no effect on other glutamate receptors.

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.

Plasticity

The ability of synapses or neurons to modify the manner in which incoming signals are received, modified, and/or transmitted.

Poly(A)-Binding Protein

A protein that links the 5′ and 3′ ends of the mRNA and promotes mRNA circularization.

Postsynaptic Density

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

Postsynaptic Density Protein-95 (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. PSD-95 is a member of the core scaffold complex of excitatory synapses.

RAB

A family of proteins, which are members of the Ras superfamily of monomeric G proteins.

RHO GTP/GDP Exchange Factor (RHO/GEF) Kalirin-7

A protein that interacts with PDZ proteins, such as PSD-95. It is involved in nerve growth and development and is important in remodeling of cortical neurons.

Ribbon Synapses

Specialized structures of synapses in sense organs of the visual, auditory, and vestibular systems.

RIBEYE

A synaptic ribbon-specific protein.

RNA Granule Protein 105 (RNG105)

A component of RNA granules that binds RNA and appears to mediate dendritic mRNA localization and local translation.

Ryanodine Receptors

Intracellular calcium channels present in muscle and neurons.

SEC1/MUNC18-like (SM) Proteins

Proteins which serve as both negative and positive regulators of the fusion machinery.

Scaffold Proteins

Proteins which bind to receptors and maintain the relationships among receptors and signaling proteins. They interact with each other to form an organizing platform for precise placement of signaling proteins.

Shank

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

Small Guanosine Triphosphate (GTP)-Binding Proteins of the RAB Family

Proteins implicated in docking, with the vesicle-associated Rab linking the vesicle to a Rab effector protein on the plasma membrane.

Soluble N-Ethylmaleimide-Sensitive Factor Attachment Protein Receptors (SNAREs)

SNARE proteins belong to a family which mediates vesicle trafficking and fusion in the secretory pathway of eukaryotic cells.

Synaptosomal-Associated Protein-25 (SNAP-25)

A soluble n-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) located on the target presynaptic membrane (t-SNARE) and involved in vesicle release.

Soluble N-ethylmaleimide-Sensitive Factor Attachment Proteins (SNAPs)

Proteins belonging to a family, which mediate vesicle trafficking and fusion in the secretory pathway of eukaryotic cells.

Synapses

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

Synaptic Protein Interaction (SYNPRINT) Site

A SNARE protein interaction site on presynaptic voltage-gated Ca²⁺ Ca_V2 channels.

Synaptic Vesicles

Small (35–50 nm) and electron-lucent structures containing non-peptide neurotransmitters.

Synaptobrevin/Vesicle-Associated Membrane Protein (VAMP)

A synaptic vesicle SNARE (v-SNARE). It is a member of the SNARE complex located on synaptic vesicles and involved in the formation of a four helical fusion complex leading to synaptic vesicle exocytosis.

Synaptosomes

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

Syntaxin

A soluble n-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) located on the target presynaptic membrane (t-SNARE) and involved in vesicle release.

Target Membrane Snares (t-SNAREs) Syntaxin and Snap-25

Two members of the SNARE complex involved in the formation of a four helical fusion complex leading to synaptic vesicle exocytosis.

Three Prime Untranslated Region (3′ UTR)

A region of mRNA that is not translated.

Treadmilling

A process whereby the plus end of an actin filament undergoes polymerization while its minus end loses G-actin monomers.

Tropomyosin

A muscle protein that ordinarily obstructs the binding sites for myosin on the thin actin filaments of skeletal muscle myofilaments.

Troponin

A muscle protein having three subunits, troponin C, troponin T, and troponin I. Calcium released from the sarcoplasmic reticulum binds to troponin C present on the thin actin myofilaments of muscle. Calcium binding causes an allosteric change in troponin T, which permits tropomyosin to move, thereby unblocking the binding sites for actin, resulting in muscle contraction. Troponin I binds to actin, keeping the actin-tropomyosin complex in place and precluding actin interaction with myosin. Troponin C action dislocates troponin I and ultimately tropomyosin, leaving the binding site on actin for myosin available.

Vacuolar-H⁺ATPase (V-ATPASE)

An enzyme which drives vesicular transport. Vacuolar-H⁺ATPase (V-ATPase), which drives vesicular transport and is responsible for the protein gradient for neurotransmitter uptake.

Wiskott-Aldrich Syndrome Protein (N-WASP)

A protein involved in signal transduction from cell surface receptors to the actin cytoskeleton.