-
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 -
British Journal of Pharmacology Jul 2021The vast majority of illicit stimulants act at monoaminergic systems, causing both psychostimulant and adverse effects. Stimulants can interact as substrates or... (Review)
Review
The vast majority of illicit stimulants act at monoaminergic systems, causing both psychostimulant and adverse effects. Stimulants can interact as substrates or antagonists at the nerve terminal monoamine transporter that mediates the reuptake of monoamines across the nerve synaptic membrane and at the vesicular monoamine transporter (VMAT-2) that mediates storage of monoamines in vesicles. Stimulants can act directly at presynaptic or postsynaptic receptors for monoamines or have indirect monoamine-mimetic actions due to the release of monoamines. Cocaine and other stimulants can acutely increase the risk of sudden cardiac death. Stimulants, particularly MDMA, in hot conditions, such as that occurring at a "rave," have caused fatalities from the consequences of hyperthermia, often compounding cardiac adverse actions. This review examines the pharmacology of the cardiovascular and temperature adverse actions of stimulants.
Topics: Biological Transport; Central Nervous System Stimulants; Cocaine; Temperature; Vesicular Monoamine Transport Proteins
PubMed: 33786822
DOI: 10.1111/bph.15465 -
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 -
Nature Neuroscience Jun 2021Transient information input to the brain leads to persistent changes in synaptic circuits, contributing to the formation of memory engrams. Pre- and postsynaptic...
Transient information input to the brain leads to persistent changes in synaptic circuits, contributing to the formation of memory engrams. Pre- and postsynaptic structures undergo coordinated functional and structural changes during this process, but how such changes are achieved by their component molecules remains largely unknown. We found that activated CaMKII, a central player of synaptic plasticity, undergoes liquid-liquid phase separation with the NMDA-type glutamate receptor subunit GluN2B. Due to CaMKII autophosphorylation, the condensate stably persists even after Ca is removed. The selective binding of activated CaMKII with GluN2B cosegregates AMPA receptors and the synaptic adhesion molecule neuroligin into a phase-in-phase assembly. In this way, Ca-induced liquid-liquid phase separation of CaMKII has the potential to act as an activity-dependent mechanism to crosslink postsynaptic proteins, which may serve as a platform for synaptic reorganization associated with synaptic plasticity.
Topics: Amino Acid Sequence; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Enzyme Activation; Female; Liquid-Liquid Extraction; Male; Membrane Proteins; Mice; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate
PubMed: 33927400
DOI: 10.1038/s41593-021-00843-3 -
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 -
Neuroscience Bulletin Feb 2021Acid-sensing ion channels (ASICs), the main H receptors in the central nervous system, sense extracellular pH fluctuations and mediate cation influx. ASIC1a, the major...
Acid-sensing ion channels (ASICs), the main H receptors in the central nervous system, sense extracellular pH fluctuations and mediate cation influx. ASIC1a, the major subunit responsible for acid-activated current, is widely expressed in brain neurons, where it plays pivotal roles in diverse functions including synaptic transmission and plasticity. However, the underlying molecular mechanisms for these functions remain mysterious. Using extracellular epitope tagging and a novel antibody recognizing the hASIC1a ectodomain, we examined the membrane targeting and dynamic trafficking of hASIC1a in cultured cortical neurons. Surface hASIC1a was distributed throughout somata and dendrites, clustered in spine heads, and co-localized with postsynaptic markers. By extracellular pHluorin tagging and fluorescence recovery after photobleaching, we detected movement of hASIC1a in synaptic spine heads. Single-particle tracking along with use of the anti-hASIC1a ectodomain antibody revealed long-distance migration and local movement of surface hASIC1a puncta on dendrites. Importantly, enhancing synaptic activity with brain-derived neurotrophic factor accelerated the trafficking and lateral mobility of hASIC1a. With this newly-developed toolbox, our data demonstrate the synaptic location and high dynamics of functionally-relevant hASIC1a on the surface of excitatory synapses, supporting its involvement in synaptic functions.
Topics: Acid Sensing Ion Channels; Neurons; Synapses; Synaptic Transmission
PubMed: 32996060
DOI: 10.1007/s12264-020-00581-9 -
Neuroscience Feb 2021Besides their primary function mediating the repolarization phase of action potentials, potassium channels exquisitely and ubiquitously regulate the resting membrane... (Review)
Review
Besides their primary function mediating the repolarization phase of action potentials, potassium channels exquisitely and ubiquitously regulate the resting membrane potential of neurons and therefore have a key role establishing their intrinsic excitability. This group of proteins is composed of a very diverse collection of voltage-dependent and -independent ion channels, whose specific distribution is finely tuned at the level of the synapse. Both at the presynaptic and postsynaptic membranes, different types of potassium channels are subjected to modulation by second messenger signaling cascades triggered by metabotropic receptors, which in this way serve as a link between neurotransmitter actions and changes in the neuron membrane excitability. On the one hand, by regulating the resting membrane potential of the postsynaptic membrane, potassium channels appear to be critical towards setting the threshold for the induction of long-term potentiation and depression. On the other hand, these channels maintain the presynaptic membrane potential under control, therefore influencing the probability of neurotransmitter release underlying different forms of short-term plasticity. In the present review, we examine in detail the role of metabotropic receptors translating their activation by different neurotransmitters into a final effect modulating several types of potassium channels. Furthermore, we evaluate the consequences that this interplay has on the induction and maintenance of different forms of synaptic plasticity.
Topics: Long-Term Potentiation; Neuronal Plasticity; Potassium Channels; Synapses; Synaptic Transmission
PubMed: 32114098
DOI: 10.1016/j.neuroscience.2020.02.025 -
Neuron Oct 2022Excitatory synapses are formed and matured by the cooperative actions of synaptic organizers, such as neurexins (Nrxns), neuroligins (Nlgns), LRRTMs, and Cbln1. Recent...
Excitatory synapses are formed and matured by the cooperative actions of synaptic organizers, such as neurexins (Nrxns), neuroligins (Nlgns), LRRTMs, and Cbln1. Recent super-resolution nanoscopy developments have revealed that many synaptic organizers, as well as glutamate receptors and glutamate release machinery, exist as nanoclusters within synapses. However, it is unclear how such nanodomains interact with each other to organize excitatory synapses in vivo. By applying X10 expansion microscopy to epitope tag knockin mice, we found that Cbln1, Nlgn1, and LRRTM1, which share Nrxn as a common presynaptic receptor, form overlapping or separate nanodomains depending on Nrxn with or without a sequence encoded by splice site 4. The size and position of glutamate receptor nanodomains of GluD1, NMDA, and AMPA receptors were regulated by Cbln1, Nlgn1, and LRRTM1 nanodomains, respectively. These findings indicate that Nrxns anterogradely regulate the postsynaptic nanoscopic architecture of glutamate receptors through competition and coordination of Nrxn ligands.
Topics: Animals; Cell Adhesion Molecules, Neuronal; Epitopes; Glutamic Acid; Ligands; Membrane Proteins; Mice; N-Methylaspartate; Nerve Tissue Proteins; Receptors, AMPA; Receptors, Glutamate; Receptors, Presynaptic; Synapses
PubMed: 36007521
DOI: 10.1016/j.neuron.2022.07.027 -
Biomolecules Nov 2021Compartmentalization of the membrane is essential for cells to perform highly specific tasks and spatially constrained biochemical functions in topographically defined... (Review)
Review
Compartmentalization of the membrane is essential for cells to perform highly specific tasks and spatially constrained biochemical functions in topographically defined areas. These membrane lateral heterogeneities range from nanoscopic dimensions, often involving only a few molecular constituents, to micron-sized mesoscopic domains resulting from the coalescence of nanodomains. Short-lived domains lasting for a few milliseconds coexist with more stable platforms lasting from minutes to days. This panoply of lateral domains subserves the great variety of demands of cell physiology, particularly high for those implicated in signaling. The dendritic spine, a subcellular structure of neurons at the receiving (postsynaptic) end of central nervous system excitatory synapses, exploits this compartmentalization principle. In its most frequent adult morphology, the mushroom-shaped spine harbors neurotransmitter receptors, enzymes, and scaffolding proteins tightly packed in a volume of a few femtoliters. In addition to constituting a mesoscopic lateral heterogeneity of the dendritic arborization, the dendritic spine postsynaptic membrane is further compartmentalized into spatially delimited nanodomains that execute separate functions in the synapse. This review discusses the functional relevance of compartmentalization and nanodomain organization in synaptic transmission and plasticity and exemplifies the importance of this parcelization in various neurotransmitter signaling systems operating at dendritic spines, using two fast ligand-gated ionotropic receptors, the nicotinic acetylcholine receptor and the glutamatergic receptor, and a second-messenger G-protein coupled receptor, the cannabinoid receptor, as paradigmatic examples.
Topics: Dendritic Spines; Neurons; Synapses; Synaptic Transmission
PubMed: 34827695
DOI: 10.3390/biom11111697