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Seminars in Cell & Developmental Biology Feb 2018The endosomal sorting complex required for transport (ESCRT) is made of subcomplexes (ESCRT 0-III), crucial to membrane remodelling at endosomes, nuclear envelope and... (Review)
Review
The endosomal sorting complex required for transport (ESCRT) is made of subcomplexes (ESCRT 0-III), crucial to membrane remodelling at endosomes, nuclear envelope and cell surface. ESCRT-III shapes membranes and in most cases cooperates with the ATPase VPS4 to mediate fission of membrane necks from the inside. The first ESCRT complexes mainly serve to catalyse the formation of ESCRT-III but can be bypassed by accessory proteins like the Alg-2 interacting protein-X (ALIX). In the nervous system, ALIX/ESCRT controls the survival of embryonic neural progenitors and later on the outgrowth and pruning of axons and dendrites, all necessary steps to establish a functional brain. In the adult brain, ESCRTs allow the endosomal turn over of synaptic vesicle proteins while stable ESCRT complexes might serve as scaffolds for the postsynaptic parts. The necessity of ESCRT for the harmonious function of the brain has its pathological counterpart, the mutations in CHMP2B of ESCRT-III giving rise to several neurodegenerative diseases.
Topics: Animals; Biological Transport; Endosomal Sorting Complexes Required for Transport; Humans; Nervous System
PubMed: 28811263
DOI: 10.1016/j.semcdb.2017.08.013 -
Current Opinion in Structural Biology Feb 2019The postsynaptic density (PSD) is a protein-rich assembly below the postsynaptic membrane, formed of large scaffolding proteins. These proteins carry a combination of... (Review)
Review
The postsynaptic density (PSD) is a protein-rich assembly below the postsynaptic membrane, formed of large scaffolding proteins. These proteins carry a combination of protein interaction domains, which may interact with several alternative partners; the structure of the protein assembly can be regulated in an activity-dependent manner. A major scaffolding molecule in the PSD is Shank, a family of three main isoforms with highly similar domain structure. Proteins of the Shank family are targets of mutations in neurological disorders, such as autism and schizophrenia. All the predicted folded domains of Shank have now been crystallized. However, for an understanding of the structure and function of full-length Shank and its complexes in the supramolecular PSD assembly, novel complementary approaches and hybrid techniques must be employed.
Topics: Animals; Humans; Nerve Tissue Proteins; Nervous System Diseases; Post-Synaptic Density; Protein Domains
PubMed: 30849620
DOI: 10.1016/j.sbi.2019.01.007 -
Neuropharmacology Sep 2021Glutamate is by far the most abundant neurotransmitter used by excitatory synapses in the vertebrate central nervous system. Once released into the synaptic cleft, it... (Review)
Review
Glutamate is by far the most abundant neurotransmitter used by excitatory synapses in the vertebrate central nervous system. Once released into the synaptic cleft, it depolarises the postsynaptic membrane and activates downstream signalling pathways resulting in the propagation of the excitatory signal. Initial depolarisation is primarily mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors. These ion channels are the first ones to be activated by released glutamate and their kinetics, dynamics and abundance on the postsynaptic membrane defines the strength of the postsynaptic response. This review focuses on native AMPA receptors and synaptic environment they inhabit and considers structural and functional properties of the receptors obtained in heterologous systems in the light of spatial and temporal constraints of the synapse. This article is part of the special Issue on 'Glutamate Receptors - AMPA receptors'.
Topics: Animals; Glutamic Acid; Humans; Receptors, AMPA; Synapses; Synaptic Membranes; Synaptic Transmission; Time Factors
PubMed: 34271021
DOI: 10.1016/j.neuropharm.2021.108711 -
Brain Research Bulletin Mar 2017Glycinergic synapses predominate in brainstem and spinal cord where they modulate motor and sensory processing. Their postsynaptic mechanisms have been considered rather... (Review)
Review
Glycinergic synapses predominate in brainstem and spinal cord where they modulate motor and sensory processing. Their postsynaptic mechanisms have been considered rather simple because they lack a large variety of glycine receptor isoforms and have relatively simple postsynaptic densities at the ultrastructural level. However, this simplicity is misleading being their postsynaptic regions regulated by a variety of complex mechanisms controlling the efficacy of synaptic inhibition. Early studies suggested that glycinergic inhibitory strength and dynamics depend largely on structural features rather than on molecular complexity. These include regulation of the number of postsynaptic glycine receptors, their localization and the amount of co-localized GABA receptors and GABA-glycine co-transmission. These properties we now know are under the control of gephyrin. Gephyrin is the first postsynaptic scaffolding protein ever discovered and it was recently found to display a large degree of variation and regulation by splice variants, posttranslational modifications, intracellular trafficking and interactions with the underlying cytoskeleton. Many of these mechanisms are governed by converging excitatory activity and regulate gephyrin oligomerization and receptor binding, the architecture of the postsynaptic density (and by extension the whole synaptic complex), receptor retention and stability. These newly uncovered molecular mechanisms define the size and number of gephyrin postsynaptic regions and the numbers and proportions of glycine and GABA receptors contained within. All together, they control the emergence of glycinergic synapses of different strength and temporal properties to best match the excitatory drive received by each individual neuron or local dendritic compartment.
Topics: Animals; Carrier Proteins; Glycine; Humans; Membrane Proteins; Neural Inhibition; Receptors, GABA-A; Receptors, Glycine; Synapses
PubMed: 27612963
DOI: 10.1016/j.brainresbull.2016.09.003 -
The Journal of General Physiology Apr 2021Spines are tiny nanoscale protrusions from dendrites of neurons. In the cortex and hippocampus, most of the excitatory postsynaptic sites reside in spines. The bulbous... (Review)
Review
Spines are tiny nanoscale protrusions from dendrites of neurons. In the cortex and hippocampus, most of the excitatory postsynaptic sites reside in spines. The bulbous spine head is connected to the dendritic shaft by a thin membranous neck. Because the neck is narrow, spine heads are thought to function as biochemically independent signaling compartments. Thus, dynamic changes in the composition, distribution, mobility, conformations, and signaling properties of molecules contained within spines can account for much of the molecular basis of postsynaptic function and regulation. A major factor in controlling these changes is the diffusional properties of proteins within this small compartment. Advances in measurement techniques using fluorescence microscopy now make it possible to measure molecular diffusion within single dendritic spines directly. Here, we review the regulatory mechanisms of diffusion in spines by local intra-spine architecture and discuss their implications for neuronal signaling and synaptic plasticity.
Topics: Dendritic Spines; Diffusion; Hippocampus; Neuronal Plasticity; Neurons; Synapses
PubMed: 33720306
DOI: 10.1085/jgp.202012814 -
Frontiers in Molecular Neuroscience 2015Changes in synaptic strength underlie the basis of learning and memory and are controlled, in part, by the insertion or removal of AMPA-type glutamate receptors at the... (Review)
Review
Changes in synaptic strength underlie the basis of learning and memory and are controlled, in part, by the insertion or removal of AMPA-type glutamate receptors at the postsynaptic membrane of excitatory synapses. Once internalized, these receptors may be recycled back to the plasma membrane by subunit-specific interactions with other proteins or by post-translational modifications such as phosphorylation. Alternatively, these receptors may be targeted for destruction by multiple degradation pathways in the cell. Ubiquitination, another post-translational modification, has recently emerged as a key signal that regulates the recycling and trafficking of glutamate receptors. In this review, we will discuss recent findings on the role of ubiquitination in the trafficking and turnover of ionotropic glutamate receptors and plasticity of excitatory synapses.
PubMed: 26528125
DOI: 10.3389/fnmol.2015.00060 -
Amino Acids Dec 2020Synaptosomes are frequently used research objects in neurobiology studies focusing on synaptic transmission as they mimic several aspects of the physiological synaptic...
Synaptosomes are frequently used research objects in neurobiology studies focusing on synaptic transmission as they mimic several aspects of the physiological synaptic functions. They contain the whole apparatus for neurotransmission, the presynaptic nerve ending with synaptic vesicles, synaptic mitochondria and often a segment of the postsynaptic membrane along with the postsynaptic density is attached to its outer surface. As being artificial functional organelles, synaptosomes are viable for several hours, retain their activity, membrane potential, and capable to store, release, and reuptake neurotransmitters. Synaptosomes are ideal subjects for proteomic analysis. The recently available separation and protein detection techniques can cope with the reduced complexity of the organelle and enable the simultaneous qualitative and quantitative analysis of thousands of proteins shaping the structural and functional characteristics of the synapse. Synaptosomes are formed during the homogenization of nervous tissue in the isoosmotic milieu and can be isolated from the homogenate by various approaches. Each enrichment method has its own benefits and drawbacks and there is not a single method that is optimal for all research purposes. For a proper proteomic experiment, it is desirable to preserve the native synaptic structure during the isolation procedure and keep the degree of contamination from other organelles or cell types as low as possible. In this article, we examined five synaptosome isolation methods from a proteomic point of view by the means of electron microscopy, Western blot, and liquid chromatography-mass spectrometry to compare their efficiency in the isolation of synaptosomes and depletion of contaminating subcellular structures. In our study, the different isolation procedures led to a largely overlapping pool of proteins with a fairly similar distribution of presynaptic, active zone, synaptic vesicle, and postsynaptic proteins; however, discrete differences were noticeable in individual postsynaptic proteins and in the number of identified transmembrane proteins. Much pronounced variance was observed in the degree of contamination with mitochondrial and glial structures. Therefore, we suggest that in selecting the appropriate isolation method for any neuroproteomics experiment carried out on synaptosomes, the degree and sort/source of contamination should be considered as a primary aspect.
Topics: Animals; Brain; Chromatography, Liquid; Humans; Mass Spectrometry; Membrane Potentials; Membrane Proteins; Microscopy, Electron; Mitochondria; Presynaptic Terminals; Proteomics; Rats; Synapses; Synaptic Transmission; Synaptosomes
PubMed: 33211194
DOI: 10.1007/s00726-020-02912-6 -
Brain Research Bulletin Mar 2017In the adult mammalian brain, GABAergic neurotransmission provides the majority of synaptic inhibition that balances glutamatergic excitatory drive and thereby controls... (Review)
Review
In the adult mammalian brain, GABAergic neurotransmission provides the majority of synaptic inhibition that balances glutamatergic excitatory drive and thereby controls neuronal output. It is generally accepted that synaptogenesis is initiated through highly specific protein-protein interactions mediated by membrane proteins expressed in developing presynaptic terminals and postsynaptic membranes. Accumulating studies have uncovered a number of membrane proteins that regulate different aspects of GABAergic synapse development. In this review, we summarize recent advances in understanding of GABAergic synapse development with a focus on postsynaptic membrane molecules, including receptors, synaptogenic cell adhesion molecules and immunoglobulin superfamily proteins.
Topics: Animals; Brain; GABAergic Neurons; Membrane Proteins; Nerve Tissue Proteins; Synapses
PubMed: 27453545
DOI: 10.1016/j.brainresbull.2016.07.004 -
Proceedings of the National Academy of... Nov 2022Robust neural information transfer relies on a delicate molecular nano-architecture of chemical synapses. Neurotransmitter release is controlled by a specific...
Robust neural information transfer relies on a delicate molecular nano-architecture of chemical synapses. Neurotransmitter release is controlled by a specific arrangement of proteins within presynaptic active zones. How the specific presynaptic molecular architecture relates to postsynaptic organization and how synaptic nano-architecture is transsynaptically regulated to enable stable synaptic transmission remain enigmatic. Using time-gated stimulated emission-depletion microscopy at the neuromuscular junction, we found that presynaptic nanorings formed by the active-zone scaffold Bruchpilot (Brp) align with postsynaptic glutamate receptor (GluR) rings. Individual rings harbor approximately four transsynaptically aligned Brp-GluR nanocolumns. Similar nanocolumn rings are formed by the presynaptic protein Unc13A and GluRs. Intriguingly, acute GluR impairment triggers transsynaptic nanocolumn formation on the minute timescale during homeostatic plasticity. We reveal distinct phases of structural transsynaptic homeostatic plasticity, with postsynaptic GluR reorganization preceding presynaptic Brp modulation. Finally, homeostatic control of transsynaptic nano-architecture and neurotransmitter release requires the auxiliary GluR subunit Neto. Thus, transsynaptic nanocolumn rings provide a substrate for rapid homeostatic stabilization of synaptic efficacy.
Topics: Animals; Neuromuscular Junction; Drosophila; Synaptic Transmission; Synapses; Receptors, Glutamate; Drosophila Proteins; Neurotransmitter Agents; Membrane Proteins
PubMed: 36322725
DOI: 10.1073/pnas.2119044119 -
Biophysical Journal Aug 2023Recently, cellular biomolecular condensates formed via phase separation have received considerable attention. While they can be formed either in cytosol (denoted as 3D)...
Recently, cellular biomolecular condensates formed via phase separation have received considerable attention. While they can be formed either in cytosol (denoted as 3D) or beneath the membrane (2D), the underlying difference between the two has not been well clarified. To compare the phase behaviors in 3D and 2D, postsynaptic density (PSD) serves as a model system. PSD is a protein condensate located under the postsynaptic membrane that influences the localization of glutamate receptors and thus contributes to synaptic plasticity. Recent in vitro studies have revealed the formation of droplets of various soluble PSD proteins via liquid-liquid phase separation. However, it is unclear how these protein condensates are formed beneath the membrane and how they specifically affect the localization of glutamate receptors in the membrane. In this study, focusing on the mixture of a glutamate receptor complex, AMPAR-TARP, and a ubiquitous scaffolding protein, PSD-95, we constructed a mesoscopic model of protein-domain interactions in PSD and performed comparative molecular simulations. The results showed a sharp contrast in the phase behaviors of protein assemblies in 3D and those under the membrane (2D). A mixture of a soluble variant of the AMPAR-TARP complex and PSD-95 in the 3D system resulted in a phase-separated condensate, which was consistent with the experimental results. However, with identical domain interactions, AMPAR-TARP embedded in the membrane formed clusters with PSD-95, but did not form a stable separated phase. Thus, the cluster formation behaviors of PSD proteins in the 3D and 2D systems were distinct. The current study suggests that, more generally, stable phase separation can be more difficult to achieve in and beneath the membrane than in 3D systems.
Topics: Neuronal Plasticity; Biomolecular Condensates; Nerve Tissue Proteins; Receptors, Glutamate; Cell Membrane; Disks Large Homolog 4 Protein; Computer Simulation; Cytosol; Phase Separation; Protein Interaction Maps; Models, Chemical
PubMed: 37496268
DOI: 10.1016/j.bpj.2023.07.015