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Neuroscience Feb 2021The postsynaptic density (PSD) is a complex subcellular domain important for postsynaptic signaling, function, and plasticity. The PSD is present at excitatory synapses... (Review)
Review
The postsynaptic density (PSD) is a complex subcellular domain important for postsynaptic signaling, function, and plasticity. The PSD is present at excitatory synapses and specialized to allow for precise neuron-to-neuron transmission of information. The PSD is localized immediately underneath the postsynaptic membrane forming a major protein network that regulates postsynaptic signaling and synaptic plasticity. Glutamatergic synaptic dysfunction affecting PSD morphology and signaling events have been described in many neurodegenerative disorders, either sporadic or familial forms. Thus, in this review we describe the main protein players forming the PSD and their activity, as well as relevant modifications in key components of the postsynaptic architecture occurring in Huntington's, Parkinson's and Alzheimer's diseases.
Topics: Humans; Neurodegenerative Diseases; Neuronal Plasticity; Post-Synaptic Density; Synapses; Synaptic Transmission
PubMed: 31887357
DOI: 10.1016/j.neuroscience.2019.12.002 -
Journal of Neurochemistry Dec 2016Proper brain function in the nervous system relies on the accurate establishment of synaptic contacts during development. Countless synapses populate the adult brain in... (Review)
Review
Proper brain function in the nervous system relies on the accurate establishment of synaptic contacts during development. Countless synapses populate the adult brain in an orderly fashion. In each synapse, a presynaptic terminal loaded with neurotransmitters-containing synaptic vesicles is perfectly aligned to an array of receptors in the postsynaptic membrane. Presynaptic differentiation, which encompasses the events underlying assembly of new presynaptic units, has seen notable advances in recent years. It is now consensual that as a growing axon encounters the receptive dendrites of its partner, presynaptic assembly will be triggered and specified by multiple postsynaptically-derived factors including soluble molecules and cell adhesion complexes. Presynaptic material that reaches these distant sites by axonal transport in the form of pre-assembled packets will be retained and clustered, ultimately giving rise to a presynaptic bouton. This review focuses on the cellular and molecular aspects of presynaptic differentiation in the central nervous system, with a particular emphasis on the identity of the instructive factors and the intracellular processes used by neuronal cells to assemble functional presynaptic terminals. We provide a detailed description of the mechanisms leading to the formation of new presynaptic terminals. In brief, soma-derived packets of pre-assembled material are trafficked to distant axonal sites. Synaptogenic factors from dendritic or glial provenance activate downstream intra-axonal mediators to trigger clustering of passing material and their correct organization into a new presynaptic bouton. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases".
Topics: Animals; Axons; Cell Differentiation; Dendrites; Humans; Presynaptic Terminals; Synapses
PubMed: 27315450
DOI: 10.1111/jnc.13702 -
Current Opinion in Neurobiology Aug 2022Dysregulation of glutamatergic synapses plays an important role in the pathogenesis of neurological diseases. In addition to mediating excitatory synaptic transmission,... (Review)
Review
Dysregulation of glutamatergic synapses plays an important role in the pathogenesis of neurological diseases. In addition to mediating excitatory synaptic transmission, postsynaptic glutamate receptors interact with various membrane and intracellular proteins. They form structural and/or signaling synaptic protein complexes and thereby play diverse postsynaptic functions. Recently, several postsynaptic protein complexes have been associated with various neurological diseases and hence, have been characterized as important therapeutic targets. Moreover, novel small molecules and therapeutic peptides targeting and modulating the activities of these protein complexes have been discovered, some of which have advanced through preclinical translational research and/or clinical studies. This article describes the recent investigation of eight key protein complexes associated with the postsynaptic ionotropic and metabotropic glutamate receptors as therapeutic targets for central nervous system diseases.
Topics: Receptors, Glutamate; Receptors, Metabotropic Glutamate; Synapses; Synaptic Transmission
PubMed: 35738196
DOI: 10.1016/j.conb.2022.102585 -
Current Opinion in Cell Biology Apr 2021Clustering is a prominent feature of receptors at the plasma membrane (PM). It plays an important role in signaling. Liquid-liquid phase separation (LLPS) of proteins is... (Review)
Review
Clustering is a prominent feature of receptors at the plasma membrane (PM). It plays an important role in signaling. Liquid-liquid phase separation (LLPS) of proteins is emerging as a novel mechanism underlying the observed clustering. Receptors/transmembrane signaling proteins can be core components essential for LLPS (such as LAT or nephrin) or clients enriched at the phase-separated condensates (for example, at the postsynaptic density or at tight junctions). Condensate formation has been shown to regulate signaling in multiple ways, including by increasing protein binding avidity and by modulating the local biochemical environment. In moving forward, it is important to study protein LLPS at the PM of living cells, its interplay with other factors underlying receptor clustering, and its signaling and functional consequences.
Topics: Cell Membrane; Humans; Protein Binding; Signal Transduction
PubMed: 33461072
DOI: 10.1016/j.ceb.2020.12.006 -
Current Opinion in Insect Science Dec 2023Insects rely on their sense of smell to navigate complex environments and make decisions regarding food and reproduction. However, in natural settings, the odors that... (Review)
Review
Insects rely on their sense of smell to navigate complex environments and make decisions regarding food and reproduction. However, in natural settings, the odors that convey this information may come mixed with environmental odors that can obscure their perception. Therefore, recognizing the presence of informative odors involves generalization and discrimination processes, which can be facilitated when there is a high contrast between stimuli, or the internal representation of the odors of interest outcompetes that of concurrent ones. The first two layers of the olfactory system, which involve the detection of odorants by olfactory receptor neurons and their encoding by the first postsynaptic partners in the antennal lobe, are critical for achieving such optimal representation. In this review, we summarize evidence indicating that experience-dependent changes adjust these two levels of the olfactory system. These changes are discussed in the context of the advantages they provide for detection of informative odors.
Topics: Animals; Olfactory Pathways; Smell; Odorants; Olfactory Receptor Neurons
PubMed: 37741614
DOI: 10.1016/j.cois.2023.101117 -
Biochemistry. Biokhimiia Oct 2018Glutamate receptors play the key role in excitatory synaptic transmission in the central nervous system (CNS). N-methyl-D-aspartate-activated glutamate receptors... (Review)
Review
Glutamate receptors play the key role in excitatory synaptic transmission in the central nervous system (CNS). N-methyl-D-aspartate-activated glutamate receptors (NMDARs) are ion channels permeable to sodium, potassium, and calcium ions that localize to the pre- and postsynaptic membranes, as well as extrasynaptic neuronal membrane. Calcium entry into dendritic spines is essential for long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission. Both LTP and LTD represent morphological and functional changes occurring in the process of memory formation. NMDAR dysfunction is associated with epilepsy, schizophrenia, migraine, dementia, and neurodegenerative diseases. Prolonged activation of extrasynaptic NMDARs causes calcium overload and apoptosis of neurons. Here, we review recent findings on the molecular mechanisms of calcium-dependent NMDAR desensitization that ensures fast modulation of NMDAR conductance in the CNS and limits calcium entry into the cells under pathological conditions. We present the data on molecular determinants related to calcium-dependent NMDAR desensitization and functional interaction of NMDARs with other ion channels and transporters. We also describe association of NMDARs with lipid membrane microdomains.
Topics: Animals; Calcium; Cytoplasm; Long-Term Potentiation; Membrane Microdomains; Protein Subunits; Receptors, N-Methyl-D-Aspartate; Sodium-Calcium Exchanger; Synapses; Synaptic Transmission
PubMed: 30472955
DOI: 10.1134/S0006297918100036 -
Neuropharmacology Dec 2021The plethora of functions of glutamate in the brain are mediated by the complementary actions of ionotropic and metabotropic glutamate receptors (mGluRs). The ionotropic... (Review)
Review
The plethora of functions of glutamate in the brain are mediated by the complementary actions of ionotropic and metabotropic glutamate receptors (mGluRs). The ionotropic glutamate receptors carry most of the fast excitatory transmission, while mGluRs modulate transmission on longer timescales by triggering multiple intracellular signaling pathways. As such, mGluRs mediate critical aspects of synaptic transmission and plasticity. Interestingly, at synapses, mGluRs operate at both sides of the cleft, and thus bidirectionally exert the effects of glutamate. At postsynaptic sites, group I mGluRs act to modulate excitability and plasticity. At presynaptic sites, group II and III mGluRs act as auto-receptors, modulating release properties in an activity-dependent manner. Thus, synaptic mGluRs are essential signal integrators that functionally couple presynaptic and postsynaptic mechanisms of transmission and plasticity. Understanding how these receptors reach the membrane and are positioned relative to the presynaptic glutamate release site are therefore important aspects of synapse biology. In this review, we will discuss the currently known mechanisms underlying the trafficking and positioning of mGluRs at and around synapses, and how these mechanisms contribute to synaptic functioning. We will highlight outstanding questions and present an outlook on how recent technological developments will move this exciting research field forward.
Topics: Animals; Glutamic Acid; Humans; Neuronal Plasticity; Neurons; Receptors, Metabotropic Glutamate; Signal Transduction; Synapses; Synaptic Transmission
PubMed: 34592242
DOI: 10.1016/j.neuropharm.2021.108799 -
Microscopy (Oxford, England) Feb 2022Many new structures of membrane proteins have been determined over the last decade, yet the nature of protein-lipid interplay has received scant attention. The...
Many new structures of membrane proteins have been determined over the last decade, yet the nature of protein-lipid interplay has received scant attention. The postsynaptic membrane of the neuromuscular junction and Torpedo electrocytes has a regular architecture, opening an opportunity to illuminate how proteins and lipids act together in a native membrane setting. Cryo electron microscopy (Cryo-EM) images show that cholesterol segregates preferentially around the constituent ion channel, the nicotinic acetylcholine receptor, interacting with specific sites in both leaflets of the bilayer. In addition to maintaining the transmembrane α-helical architecture, cholesterol forms microdomains - bridges of rigid sterol groups that link one channel to the next. This article discusses the whole protein-lipid organization of the cholinergic postsynaptic membrane, its physiological implications and how the observed details relate to our current concept of the membrane structure. I suggest that cooperative interactions, facilitated by the regular protein-lipid arrangement, help to spread channel activation into regions distant from the sites of neurotransmitter release, thereby enhancing the postsynaptic response.
Topics: Animals; Cell Membrane; Cholesterol; Neuromuscular Junction; Receptors, Nicotinic; Torpedo
PubMed: 34226930
DOI: 10.1093/jmicro/dfab023 -
Cellular Signalling Dec 2020The postsynaptic density (PSD) plays an essential role in the organization of the synaptic signaling machinery. It contains a set of core scaffolding proteins that... (Review)
Review
The postsynaptic density (PSD) plays an essential role in the organization of the synaptic signaling machinery. It contains a set of core scaffolding proteins that provide the backbone to PSD protein-protein interaction networks (PINs). These core scaffolding proteins can be seen as three principal layers classified by protein family, with DLG proteins being at the top, SHANKs along the bottom, and DLGAPs connecting the two layers. Early studies utilizing yeast two hybrid enabled the identification of direct protein-protein interactions (PPIs) within the multiple layers of scaffolding proteins. More recently, mass-spectrometry has allowed the characterization of whole interactomes within the PSD. This expansion of knowledge has further solidified the centrality of core scaffolding family members within synaptic PINs and provided context for their role in neuronal development and synaptic function. Here, we discuss the scaffolding machinery of the PSD, their essential functions in the organization of synaptic PINs, along with their relationship to neuronal processes found to be impaired in complex brain disorders.
Topics: Animals; Cell Line; Humans; Membrane Proteins; Nerve Tissue Proteins; Post-Synaptic Density; Protein Binding; Protein Interaction Domains and Motifs; Synapses
PubMed: 32941943
DOI: 10.1016/j.cellsig.2020.109782 -
Frontiers in Synaptic Neuroscience 2021The precise subsynaptic organization of proteins at the postsynaptic membrane controls synaptic transmission. In particular, postsynaptic receptor complexes are... (Review)
Review
The precise subsynaptic organization of proteins at the postsynaptic membrane controls synaptic transmission. In particular, postsynaptic receptor complexes are concentrated in distinct membrane nanodomains to optimize synaptic signaling. However, despite the clear functional relevance of subsynaptic receptor organization to synaptic transmission and plasticity, the mechanisms that underlie the nanoscale organization of the postsynaptic membrane remain elusive. Over the last decades, the field has predominantly focused on the role of protein-protein interactions in receptor trafficking and positioning in the synaptic membrane. In contrast, the contribution of lipids, the principal constituents of the membrane, to receptor positioning at the synapse remains poorly understood. Nevertheless, there is compelling evidence that the synaptic membrane is enriched in specific lipid species and that deregulation of lipid homeostasis in neurons severely affects synaptic functioning. In this review we focus on how lipids are organized at the synaptic membrane, with special emphasis on how current models of membrane organization could contribute to protein distribution at the synapse and synaptic transmission. Finally, we will present an outlook on how novel technical developments could be applied to study the dynamic interplay between lipids and proteins at the postsynaptic membrane.
PubMed: 34887741
DOI: 10.3389/fnsyn.2021.790773