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Journal of Thrombosis and Haemostasis :... Jan 2019The blood vessel wall has a number of self-healing properties, enabling it to minimize blood loss and prevent or overcome infections in the event of vascular trauma.... (Review)
Review
The blood vessel wall has a number of self-healing properties, enabling it to minimize blood loss and prevent or overcome infections in the event of vascular trauma. Endothelial cells prepackage a cocktail of hemostatic, inflammatory and angiogenic mediators in their unique secretory organelles, the Weibel-Palade bodies (WPBs), which can be immediately released on demand. Secretion of their contents into the vascular lumen through a process called exocytosis enables the endothelium to actively participate in the arrest of bleeding and to slow down and direct leukocytes to areas of inflammation. Owing to their remarkable elongated morphology and their secretory contents, which span the entire size spectrum of small chemokines all the way up to ultralarge von Willebrand factor multimers, WPBs constitute an ideal model system for studying the molecular mechanisms of secretory organelle biogenesis, exocytosis, and content expulsion. Recent studies have now shown that, during exocytosis, WPBs can undergo several distinct modes of fusion, and can utilize fundamentally different mechanisms to expel their contents. In this article, we discuss recent advances in our understanding of the composition of the WPB exocytotic machinery and how, because of its configuration, it is able to support WPB release in its various forms.
Topics: Animals; Endothelial Cells; Exocytosis; Hemostasis; Humans; Secretory Pathway; Signal Transduction; Weibel-Palade Bodies; von Willebrand Factor
PubMed: 30375718
DOI: 10.1111/jth.14322 -
Physiological Reviews Oct 2006At a given cytosolic domain of a chromaffin cell, the rate and amplitude of the Ca2+ concentration ([Ca2+]c) depends on at least four efficient regulatory systems: 1)... (Review)
Review
At a given cytosolic domain of a chromaffin cell, the rate and amplitude of the Ca2+ concentration ([Ca2+]c) depends on at least four efficient regulatory systems: 1) plasmalemmal calcium channels, 2) endoplasmic reticulum, 3) mitochondria, and 4) chromaffin vesicles. Different mammalian species express different levels of the L, N, P/Q, and R subtypes of high-voltage-activated calcium channels; in bovine and humans, P/Q channels predominate, whereas in felines and murine species, L-type channels predominate. The calcium channels in chromaffin cells are regulated by G proteins coupled to purinergic and opiate receptors, as well as by voltage and the local changes of [Ca2+]c. Chromaffin cells have been particularly useful in studying calcium channel current autoregulation by materials coreleased with catecholamines, such as ATP and opiates. Depending on the preparation (cultured cells, adrenal slices) and the stimulation pattern (action potentials, depolarizing pulses, high K+, acetylcholine), the role of each calcium channel in controlling catecholamine release can change drastically. Targeted aequorin and confocal microscopy shows that Ca2+ entry through calcium channels can refill the endoplasmic reticulum (ER) to nearly millimolar concentrations, and causes the release of Ca2+ (CICR). Depending on its degree of filling, the ER may act as a sink or source of Ca2+ that modulates catecholamine release. Targeted aequorins with different Ca2+ affinities show that mitochondria undergo surprisingly rapid millimolar Ca2+ transients, upon stimulation of chromaffin cells with ACh, high K+, or caffeine. Physiological stimuli generate [Ca2+]c microdomains in which the local subplasmalemmal [Ca2+]c rises abruptly from 0.1 to approximately 50 microM, triggering CICR, mitochondrial Ca2+ uptake, and exocytosis at nearby secretory active sites. The fact that protonophores abolish mitochondrial Ca2+ uptake, and increase catecholamine release three- to fivefold, support the earlier observation. This increase is probably due to acceleration of vesicle transport from a reserve pool to a ready-release vesicle pool; this transport might be controlled by Ca2+ redistribution to the cytoskeleton, through CICR, and/or mitochondrial Ca2+ release. We propose that chromaffin cells have developed functional triads that are formed by calcium channels, the ER, and the mitochondria and locally control the [Ca2+]c that regulate the early and late steps of exocytosis.
Topics: Adrenal Glands; Animals; Calcium Signaling; Chromaffin Cells; Exocytosis; Humans
PubMed: 17015485
DOI: 10.1152/physrev.00039.2005 -
Journal of Neurochemistry Dec 2016The molecular mechanisms for calcium-triggered membrane fusion have long been sought for, and detailed models now exist that account for at least some of the functions... (Review)
Review
The molecular mechanisms for calcium-triggered membrane fusion have long been sought for, and detailed models now exist that account for at least some of the functions of the many proteins involved in the process. Key players in the fusion reaction are a group of proteins that, upon binding to calcium, trigger the merger of cargo-filled vesicles with the plasma membrane. Low-affinity, fast-kinetics calcium sensors of the synaptotagmin family - especially synaptotagmin-1 and synaptotagmin-2 - are the main calcium sensors for fast exocytosis triggering in many cell types. Their functions extend beyond fusion triggering itself, having been implicated in the calcium-dependent vesicle recruitment during activity, docking of vesicles to the plasma membrane and priming, and even in post-fusion steps, such as fusion pore expansion and endocytosis. Furthermore, synaptotagmin diversity imparts distinct properties to the release process itself. Other calcium-sensing proteins such as Munc13s and protein kinase C play important, but more indirect roles in calcium-triggered exocytosis. Because of their higher affinity, but intrinsic slower kinetics, they operate on longer temporal and spatial scales to organize assembly of the release machinery. Finally, the high-affinity synaptotagmin-7 and Doc2 (Double C2-domain) proteins are able to trigger membrane fusion in vitro, but cellular measurements in different systems show that they may participate in either fusion or vesicle priming. Here, we summarize the properties and possible interplay of (some of) the major C2-domain containing calcium sensors in calcium-triggered exocytosis. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases".
Topics: Animals; Calcium; Calcium Channels; Calcium Signaling; Exocytosis; Humans; Neurosecretory Systems; Synaptotagmins
PubMed: 27731902
DOI: 10.1111/jnc.13865 -
Advanced Science (Weinheim,... Mar 2022To exert their therapeutic effects, nanoparticles (NPs) often need to travel into the tissues composed of multilayered cells. Accumulative evidence has revealed the...
To exert their therapeutic effects, nanoparticles (NPs) often need to travel into the tissues composed of multilayered cells. Accumulative evidence has revealed the crucial role of transcellular transport route (entry into one cell, exocytosis, and re-entry into another) in this process. While NP endocytosis and subcellular transport are intensively characterized, the exocytosis and re-entry steps are poorly understood, which becomes a barrier for NP delivery into complex tissues. Here, the authors term the exocytosis and re-entry steps together as intercellular exchange. A collagen-based three-dimension assay is developed to specifically quantify the intercellular exchange of NPs, and distinguish the contributions of several potential mechanisms. The authors show that NPs can be exocytosed freely or enclosed inside extracellular vesicles (EVs) for re-entry, while direct cell-cell contact is hardly involved. EVs account for a significant fraction of NP intercellular exchange, and its importance in NP transport is demonstrated in vitro and in vivo. While freely released NPs engage with the same receptors for re-entry, EV-enclosed ones bypass this dependence. These studies provide an easy and precise system to investigate the intercellular exchange stage of NP delivery, and shed the first light in the importance of EVs in NP transport between cells and into complex tissues.
Topics: Endocytosis; Exocytosis; Extracellular Vesicles; Nanoparticles; Transcytosis
PubMed: 35243822
DOI: 10.1002/advs.202102441 -
Traffic (Copenhagen, Denmark) Apr 2004Exocytosis is the process whereby intracellular fluid-filled vesicles fuse with the plasma membrane, incorporating vesicle proteins and lipids into the plasma membrane... (Review)
Review
Exocytosis is the process whereby intracellular fluid-filled vesicles fuse with the plasma membrane, incorporating vesicle proteins and lipids into the plasma membrane and releasing vesicle contents into the extracellular milieu. Exocytosis can occur constitutively or can be tightly regulated, for example, neurotransmitter release from nerve endings. The last two decades have witnessed the identification of a vast array of proteins and protein complexes essential for exocytosis. SNARE proteins fill the spotlight as probable mediators of membrane fusion, whereas proteins such as munc18/nsec1, NSF and SNAPs function as essential SNARE regulators. A central question that remains unanswered is how exocytic proteins and protein complexes are spatially regulated. Recent studies suggest that lipid rafts, cholesterol and sphingolipid-rich microdomains, enriched in the plasma membrane, play an essential role in regulated exocytosis pathways. The association of SNAREs with lipid rafts acts to concentrate these proteins at defined sites of the plasma membrane. Furthermore, cholesterol depletion inhibits regulated exocytosis, suggesting that lipid raft domains play a key role in the regulation of exocytosis. This review examines the role of lipid rafts in regulated exocytosis, from a passive role as spatial coordinator of exocytic proteins to a direct role in the membrane fusion reaction.
Topics: Animals; Cholesterol; Exocytosis; Humans; Membrane Microdomains; Models, Biological; Protein Conformation; Proteins; SNARE Proteins; Vesicular Transport Proteins; Viruses
PubMed: 15030567
DOI: 10.1111/j.1600-0854.2004.0162.x -
Physiological Reviews Oct 2002Most synapses rely on regulated exocytosis for determining the concentration of transmitter in the synaptic cleft. However, this mechanism may not be universal. Several... (Review)
Review
Most synapses rely on regulated exocytosis for determining the concentration of transmitter in the synaptic cleft. However, this mechanism may not be universal. Several synapses in the retina appear to use a synaptic machinery in which transmitter transporters play an essential role. Two types of transport-mediated synapses have been proposed. These synapses have been best observed in horizontal cells and cones of nonmammalian retinas. Horizontal cells use a transporter to mediate a bidirectional shuttle, whose balance point is set by ion concentrations and voltage. Nonmammalian cones combine exocytosis and the activity of a transporter. Because exocytosis is voltage independent over most of a cone's physiological voltage range, a voltage-dependent transporter determines the concentration of transmitter in the synaptic cleft. These two synapses may be models for transport-mediated synapses that operate in other parts of the brain.
Topics: Animals; Biological Transport, Active; Carrier Proteins; Exocytosis; Humans; Neurotransmitter Agents; Retina; Retinal Cone Photoreceptor Cells; Synapses
PubMed: 12270946
DOI: 10.1152/physrev.00010.2002 -
Cell Reports Aug 2023The complex morphology of neurons poses a challenge for proteostasis because the majority of lysosomal degradation machinery is present in the cell soma. In recent...
The complex morphology of neurons poses a challenge for proteostasis because the majority of lysosomal degradation machinery is present in the cell soma. In recent years, however, mature lysosomes were identified in dendrites, and a fraction of those appear to fuse with the plasma membrane and release their content to the extracellular space. Here, we report that dendritic lysosomes are heterogeneous in their composition and that only those containing lysosome-associated membrane protein (LAMP) 2A and 2B fuse with the membrane and exhibit activity-dependent motility. Exocytotic lysosomes dock in close proximity to GluN2B-containing N-methyl-D-aspartate-receptors (NMDAR) via an association of LAMP2B to the membrane-associated guanylate kinase family member SAP102/Dlg3. NMDAR-activation decreases lysosome motility and promotes membrane fusion. We find that chaperone-mediated autophagy is a supplier of content that is released to the extracellular space via lysosome exocytosis. This mechanism enables local disposal of aggregation-prone proteins like TDP-43 and huntingtin.
Topics: Chaperone-Mediated Autophagy; Guanylate Kinases; Exocytosis; Lysosomes; Dendrites
PubMed: 37590146
DOI: 10.1016/j.celrep.2023.112998 -
Platelets Mar 2017Secretion is essential to many of the roles that platelets play in the vasculature, e.g., thrombosis, angiogenesis, and inflammation, enabling platelets to modulate the... (Review)
Review
Secretion is essential to many of the roles that platelets play in the vasculature, e.g., thrombosis, angiogenesis, and inflammation, enabling platelets to modulate the microenvironment at sites of vascular lesions with a myriad of bioactive molecules stored in their granules. Past studies demonstrate that granule cargo release is mediated by Soluble NSF Attachment Protein Receptor (SNARE) proteins, which are required for granule-plasma membrane fusion. Several SNARE regulators, which control when, where, and how the SNAREs interact, have been identified in platelets. Additionally, platelet SNAREs are controlled by post-translational modifications, e.g., phosphorylation and acylation. Although there have been many recent insights into the mechanisms of platelet secretion, many questions remain: have we identified all the important regulators, does calcium directly control the process, and is platelet secretion polarized. In this review, we focus on the mechanics of platelet secretion and discuss how the secretory machinery functions in the pathway leading to membrane fusion and cargo release.
Topics: Animals; Blood Platelets; Cytoplasmic Granules; Exocytosis; Humans; Membrane Fusion; SNARE Proteins; Transport Vesicles
PubMed: 27848265
DOI: 10.1080/09537104.2016.1240768 -
Biochimica Et Biophysica Acta Aug 2003Exocytic fusion reactions triggered by Ca(2+) are widespread in neural, endocrine, exocrine, hemapoetic and perhaps all cell types. These processes exhibit tremendous... (Review)
Review
Exocytic fusion reactions triggered by Ca(2+) are widespread in neural, endocrine, exocrine, hemapoetic and perhaps all cell types. These processes exhibit tremendous variation in latencies to fusion following a Ca(2+) rise and in rates of fusion. We review reported differences for synaptic vesicle (SV) and dense-core vesicle (DCV) exocytosis and attempt to identify key features in the molecular mechanisms of docking, priming and fusion of SVs and DCVs that may account for differences in speed.
Topics: Animals; Calcium; Cell Membrane; Exocytosis; Humans; Secretory Vesicles; Synaptic Vesicles
PubMed: 12914956
DOI: 10.1016/s0167-4889(03)00093-4 -
Brain Research Reviews May 2010Gliotransmitters are chemicals released from glial cells fulfilling a following set of criteria: (i) they are synthesized by and/or stored in glia; (ii) their regulated... (Review)
Review
Gliotransmitters are chemicals released from glial cells fulfilling a following set of criteria: (i) they are synthesized by and/or stored in glia; (ii) their regulated release is triggered by physiological and/or pathological stimuli; (iii) they activate rapid (milliseconds to seconds) responses in neighboring cells; and (iv) they play a role in (patho)physiological processes. Astrocytes can release a variety of gliotransmitters into the extracellular space using several different mechanisms. In this review, we focus on exocytotic mechanism(s) underlying the release of three classes of gliotransmitters: (i) amino acids, such as, glutamate and d-serine; (ii) nucleotides, like adenosine 5'-triphosphate; and (iii) peptides, such as, atrial natriuretic peptide and brain-derived neurotrophic factor. It is becoming clear that astrocytes are endowed with elements that qualify them as cells communicating with neurons and other cells within the central nervous system by employing regulated exocytosis.
Topics: Adenosine Triphosphate; Amino Acids; Astrocytes; Exocytosis; Humans; Peptides; Signal Transduction
PubMed: 19948188
DOI: 10.1016/j.brainresrev.2009.11.008