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Neuron Jul 2012Neurotransmitters are released by synaptic vesicle exocytosis at the active zone of a presynaptic nerve terminal. In this review, I discuss the molecular composition and... (Review)
Review
Neurotransmitters are released by synaptic vesicle exocytosis at the active zone of a presynaptic nerve terminal. In this review, I discuss the molecular composition and function of the active zone. Active zones are composed of an evolutionarily conserved protein complex containing as core constituents RIM, Munc13, RIM-BP, α-liprin, and ELKS proteins. This complex docks and primes synaptic vesicles for exocytosis, recruits Ca(2+) channels to the site of exocytosis, and positions the active zone exactly opposite to postsynaptic specializations via transsynaptic cell-adhesion molecules. Moreover, this complex mediates short- and long-term plasticity in response to bursts of action potentials, thus critically contributing to the computational power of a synapse.
Topics: Animals; Exocytosis; Humans; Neuronal Plasticity; Neurotransmitter Agents; Presynaptic Terminals; Synaptic Transmission; Synaptic Vesicles
PubMed: 22794257
DOI: 10.1016/j.neuron.2012.06.012 -
Cell Nov 2006Membrane traffic in eukaryotic cells involves transport of vesicles that bud from a donor compartment and fuse with an acceptor compartment. Common principles of budding...
Membrane traffic in eukaryotic cells involves transport of vesicles that bud from a donor compartment and fuse with an acceptor compartment. Common principles of budding and fusion have emerged, and many of the proteins involved in these events are now known. However, a detailed picture of an entire trafficking organelle is not yet available. Using synaptic vesicles as a model, we have now determined the protein and lipid composition; measured vesicle size, density, and mass; calculated the average protein and lipid mass per vesicle; and determined the copy number of more than a dozen major constituents. A model has been constructed that integrates all quantitative data and includes structural models of abundant proteins. Synaptic vesicles are dominated by proteins, possess a surprising diversity of trafficking proteins, and, with the exception of the V-ATPase that is present in only one to two copies, contain numerous copies of proteins essential for membrane traffic and neurotransmitter uptake.
Topics: Animals; Lipids; Models, Molecular; Protein Transport; Proteins; Rats; Spectrometry, Fluorescence; Synaptic Vesicles
PubMed: 17110340
DOI: 10.1016/j.cell.2006.10.030 -
Neuroscience Letters Apr 2019As the sites of communication between neurons, synapses depend upon precisely regulated protein-protein interactions to support neurotransmitter release and reception.... (Review)
Review
As the sites of communication between neurons, synapses depend upon precisely regulated protein-protein interactions to support neurotransmitter release and reception. Moreover, neuronal synapses typically exist great distances (i.e. up to meters) away from cell bodies, which are the sources of new proteins and the major sites of protein degradation via lysosomes. Thus, synapses are uniquely sensitive to disruptions in proteostasis, and depend upon carefully orchestrated degradative mechanisms for the clearance of dysfunctional proteins. One of the primary cellular degradative pathways is macroautophagy, hereafter referred to as 'autophagy'. Although it has only recently become a focus of research in synaptic biology, emerging studies indicate that autophagy has essential functions at the synapse throughout an organism's lifetime. This review will discuss recent findings about the roles of synaptic autophagy, as well as some of the questions and issues to be considered in this field moving forward.
Topics: Animals; Autophagy; Humans; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 29802916
DOI: 10.1016/j.neulet.2018.05.033 -
Current Biology : CB Nov 2014Synapses are specialized asymmetric cell-cell connections permitting the controlled transfer of an electrical or chemical signal between a presynaptic neuronal cell and...
Synapses are specialized asymmetric cell-cell connections permitting the controlled transfer of an electrical or chemical signal between a presynaptic neuronal cell and a postsynaptic target cell (e.g. neuron or muscle). Adequate synapse function is an essential prerequisite of all neuronal processing, including higher cognitive functions, such as learning and memory. At synapses, neurotransmitters (e.g. amino acids, amines, peptides, and acetylcholine) are released from synaptic vesicles into the synaptic cleft in response to action potentials. The Nobel Prize for Physiology and Medicine in 2013 was awarded to James E. Rothman, Randy W. Schekman and Thomas C. Südhof "for their discoveries of the machinery regulating vesicle traffic, a major transport system in our cells". This included crucial revelations, such as the identification of the core machinery of synaptic vesicle fusion. However, in contrast to the advances concerning the organization of the core functions of the synapse, our current understanding of the processes of synapse formation and maintenance--i.e. 'synaptogenesis'--is still somewhat fragmentary. Here, we will outline the current status and future directions of the field of synaptogenesis, primarily from the perspective of the presynaptic release site.
Topics: Biological Transport; Models, Biological; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 25458214
DOI: 10.1016/j.cub.2014.10.024 -
Cold Spring Harbor Perspectives in... Sep 2012Neurons can sustain high rates of synaptic transmission without exhausting their supply of synaptic vesicles. This property relies on a highly efficient local endocytic... (Review)
Review
Neurons can sustain high rates of synaptic transmission without exhausting their supply of synaptic vesicles. This property relies on a highly efficient local endocytic recycling of synaptic vesicle membranes, which can be reused for hundreds, possibly thousands, of exo-endocytic cycles. Morphological, physiological, molecular, and genetic studies over the last four decades have provided insight into the membrane traffic reactions that govern this recycling and its regulation. These studies have shown that synaptic vesicle endocytosis capitalizes on fundamental and general endocytic mechanisms but also involves neuron-specific adaptations of such mechanisms. Thus, investigations of these processes have advanced not only the field of synaptic transmission but also, more generally, the field of endocytosis. This article summarizes current information on synaptic vesicle endocytosis with an emphasis on the underlying molecular mechanisms and with a special focus on clathrin-mediated endocytosis, the predominant pathway of synaptic vesicle protein internalization.
Topics: Actin Cytoskeleton; Clathrin; Clathrin-Coated Vesicles; Endocytosis; Exocytosis; Intracellular Membranes; Membrane Fusion; Models, Biological; Phosphatidylinositols; Protein Transport; Synaptic Transmission; Synaptic Vesicles
PubMed: 22763746
DOI: 10.1101/cshperspect.a005645 -
Traffic (Copenhagen, Denmark) Jan 2010The stoned proteins, stoned A (STNA) and stoned B (STNB), are essential for normal vesicle trafficking in Drosophila melanogaster neurons, and deletion of the stoned... (Review)
Review
The stoned proteins, stoned A (STNA) and stoned B (STNB), are essential for normal vesicle trafficking in Drosophila melanogaster neurons, and deletion of the stoned locus is lethal. Although there is a growing body of research aimed at defining the roles of these proteins, particularly for STNB where homologues have now been identified in all multicellular species, their functions and mechanisms of action are not yet established. The two proteins are structurally unrelated, consistent with two distinct cellular functions. The evidence suggests a critical requirement for stoned proteins in recycling/regulation or specification of a competent synaptic vesicle pool. As stoned proteins may be specific to a particular pathway of endocytosis, studies of their function are likely to be valuable in distinguishing between the different mechanisms of membrane retrieval and their respective contributions to synaptic vesicle recycling, a subject of considerable scientific debate. In this review, we examine the published literature on stoned and comment on the available data, conclusions from these analyses and how they may relate to alternative models of vesicle cycling.
Topics: Animals; Carrier Proteins; Drosophila Proteins; Drosophila melanogaster; Endocytosis; Exocytosis; Humans; Models, Biological; Nerve Tissue Proteins; Protein Structure, Tertiary; Protein Transport; Synaptic Vesicles
PubMed: 19883395
DOI: 10.1111/j.1600-0854.2009.00999.x -
Journal of Neurochemistry Apr 2021The revolution in genetic technology has ushered in a new age for our understanding of the underlying causes of neurodevelopmental, neuromuscular and neurodegenerative... (Review)
Review
The revolution in genetic technology has ushered in a new age for our understanding of the underlying causes of neurodevelopmental, neuromuscular and neurodegenerative disorders, revealing that the presynaptic machinery governing synaptic vesicle fusion is compromised in many of these neurological disorders. This builds upon decades of research showing that disturbance to neurotransmitter release via toxins can cause acute neurological dysfunction. In this review, we focus on disorders of synaptic vesicle fusion caused either by toxic insult to the presynapse or alterations to genes encoding the key proteins that control and regulate fusion: the SNARE proteins (synaptobrevin, syntaxin-1 and SNAP-25), Munc18, Munc13, synaptotagmin, complexin, CSPα, α-synuclein, PRRT2 and tomosyn. We discuss the roles of these proteins and the cellular and molecular mechanisms underpinning neurological deficits in these disorders.
Topics: Animals; Exocytosis; Humans; Membrane Fusion; Neurons; Synaptic Transmission; Synaptic Vesicles; Synaptotagmins
PubMed: 32916768
DOI: 10.1111/jnc.15181 -
Cell Reports Apr 2022α-synuclein, β-synuclein, and γ-synuclein are abundantly expressed proteins in the vertebrate nervous system. α-synuclein functions in neurotransmitter release by...
α-synuclein, β-synuclein, and γ-synuclein are abundantly expressed proteins in the vertebrate nervous system. α-synuclein functions in neurotransmitter release by binding to and clustering synaptic vesicles and chaperoning SNARE-complex assembly. Pathologically, aggregates originating from soluble pools of α-synuclein are deposited into Lewy bodies in Parkinson's disease and related synucleinopathies. The functions of β-synuclein and γ-synuclein in presynaptic terminals remain poorly studied. Using in vitro liposome binding studies, circular dichroism spectroscopy, immunoprecipitation, and fluorescence resonance energy transfer (FRET) experiments on isolated synaptic vesicles in combination with subcellular fractionation of brains from synuclein mouse models, we show that β-synuclein and γ-synuclein have a reduced affinity toward synaptic vesicles compared with α-synuclein, and that heteromerization of β-synuclein or γ-synuclein with α-synuclein results in reduced synaptic vesicle binding of α-synuclein in a concentration-dependent manner. Our data suggest that β-synuclein and γ-synuclein are modulators of synaptic vesicle binding of α-synuclein and thereby reduce α-synuclein's physiological activity at the neuronal synapse.
Topics: Animals; Mice; Presynaptic Terminals; Synaptic Vesicles; alpha-Synuclein; beta-Synuclein; gamma-Synuclein
PubMed: 35417693
DOI: 10.1016/j.celrep.2022.110675 -
Trends in Neurosciences Apr 2023Neuronal communication crucially relies on exocytosis of neurotransmitters from synaptic vesicles (SVs) which are clustered at synapses. To ensure reliable... (Review)
Review
Neuronal communication crucially relies on exocytosis of neurotransmitters from synaptic vesicles (SVs) which are clustered at synapses. To ensure reliable neurotransmitter release, synapses need to maintain an adequate pool of SVs at all times. Decades of research have established that SVs are clustered by synapsin 1, an abundant SV-associated phosphoprotein. The classical view postulates that SVs are crosslinked in a scaffold of protein-protein interactions between synapsins and their binding partners. Recent studies have shown that synapsins cluster SVs via liquid-liquid phase separation (LLPS), thus providing a new framework for the organization of the synapse. We discuss the evidence for phase separation of SVs, emphasizing emerging questions related to its regulation, specificity, and reversibility.
Topics: Humans; Synaptic Vesicles; Synapsins; Synapses; Synaptic Transmission; Biology
PubMed: 36725404
DOI: 10.1016/j.tins.2023.01.001 -
FEBS Letters Nov 2018In presynaptic nerve terminals, synaptic vesicles are recycled locally via an evolutionarily conserved process that ensures maintenance of neurotransmission as well as... (Review)
Review
In presynaptic nerve terminals, synaptic vesicles are recycled locally via an evolutionarily conserved process that ensures maintenance of neurotransmission as well as structural integrity of synapses. Temperature is a key environmental factor that impacts critical steps involved in fusion, endocytosis and transport in different vesicle trafficking pathways. In neurons, temperature changes have been shown to impact synaptic vesicle recycling and synaptic efficacy. But contrary to non-neuronal systems, the temperature dependence of the steps involved in fusion, endocytosis and recycling of synaptic vesicles in presynaptic terminals is not completely understood, and the existing data remain highly debated. In this Review, we discuss the implications of biophysical, biochemical and functional findings on temperature dependence of membrane retrieval in multiple systems. We propose that systematic investigation of the temperature dependence of the presynaptic vesicle trafficking process can provide novel insight into poorly understood mechanisms that govern synaptic vesicle trafficking under diverse physiological conditions.
Topics: Animals; Endocytosis; Humans; Neurons; Presynaptic Terminals; Synapses; Synaptic Transmission; Synaptic Vesicles; Temperature; Time Factors
PubMed: 30311950
DOI: 10.1002/1873-3468.13268