Synaptic Transmission in the Immune System

e-Neuroforum ◽  
2017 ◽  
Vol 23 (4) ◽  
Author(s):  
Jens Rettig ◽  
David R. Stevens
Keyword(s):  
Nervous System ◽  
Immune System ◽  
Synaptic Transmission ◽  
Molecular Mechanisms ◽  
Secretory Granules ◽  
Neuroendocrine Cells ◽  
Regulated Exocytosis ◽  
Protein Receptor ◽  
Immunological Synapses ◽  
Immunological Diseases

AbstractThe release of neurotransmitters at synapses belongs to the most important processes in the central nervous system. In the last decades much has been learned about the molecular mechanisms which form the basis for this fundamental process. Highly regulated exocytosis, based on the SNARE (soluble N-ethylmaleimide-sensitive attachment protein receptor) complex and its regulatory molecules is the signature specialization of the nervous system and is shared by neurons and neuroendocrine cells. Cells of the immune system use a similar mechanism to release cytotoxic materials from secretory granules at contacts with virally or bacterially infected cells or cancer cells, in order to remove these threats. These contact zones have been termed immunological synapses in reference to the highly specific targeted exocytosis of effector molecules. Recent findings indicate that mutations in SNARE or SNARE-interacting proteins are the basis of a number of devastating immunological diseases. While SNARE complexes are ubiquitous and mediate a wide variety of membrane fusion events it is surprising that in many cases the SNARE proteins involved in immunological synapses are the same molecules which mediate regulated exocytosis of transmitters and hormones in neurons and neuroendocrine cells. These similarities raise the possibility that results obtained at immunological synapses may be applicable, in particular in the area of presynaptic function, to neuronal synapses. Since immunological synapses (IS) are assembled and disassembled in about a half an hour, the use of immune cells isolated from human blood allows not only the study of the molecular mechanisms of synaptic transmission in human cells, but is particularly suited to the examination of the assembly and disassembly of these “synapses” via live imaging. In this overview we discuss areas of similarity between synapses of the nervous and immune systems and in the process will refer to results of our experiments of the last few years.

scholarly journals Anaphylactic Degranulation of Mast Cells: Focus on Compound Exocytosis

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Ofir Klein ◽  
Ronit Sagi-Eisenberg
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Molecular Mechanisms ◽  
Secretory Granules ◽  
Cell Types ◽  
Secretory Cells ◽  
Regulated Exocytosis ◽  
Open Questions ◽  
Conflicting Evidence ◽  
Compound Exocytosis

Anaphylaxis is a notorious type 2 immune response which may result in a systemic response and lead to death. A precondition for the unfolding of the anaphylactic shock is the secretion of inflammatory mediators from mast cells in response to an allergen, mostly through activation of the cells via the IgE-dependent pathway. While mast cells are specialized secretory cells that can secrete through a variety of exocytic modes, the most predominant mode exerted by the mast cell during anaphylaxis is compound exocytosis—a specialized form of regulated exocytosis where secretory granules fuse to one another. Here, we review the modes of regulated exocytosis in the mast cell and focus on compound exocytosis. We review historical landmarks in the research of compound exocytosis in mast cells and the methods available for investigating compound exocytosis. We also review the molecular mechanisms reported to underlie compound exocytosis in mast cells and expand further with reviewing key findings from other cell types. Finally, we discuss the possible reasons for the mast cell to utilize compound exocytosis during anaphylaxis, the conflicting evidence in different mast cell models, and the open questions in the field which remain to be answered.

scholarly journals Molecular mechanisms involved in the interaction between the immune system and nervous system

2013 ◽  
Vol 141 (1) ◽  
pp. 27-31
Author(s):  
Yoshiki Yanagawa ◽  
Yasunori Kubo ◽  
Machiko Matsumoto ◽  
Hiroko Togashi
Keyword(s):  
Nervous System ◽  
Immune System ◽  
Molecular Mechanisms

scholarly journals Chromogranin A Induces the Biogenesis of Granules with Calcium- and Actin-Dependent Dynamics and Exocytosis in Constitutively Secreting Cells

Endocrinology ◽  
2012 ◽  
Vol 153 (9) ◽  
pp. 4444-4456 ◽  
Author(s):  
Salah Elias ◽  
Charlène Delestre ◽  
Stéphane Ory ◽  
Sébastien Marais ◽  
Maïté Courel ◽  
...  
Keyword(s):  
Molecular Motors ◽  
Chromogranin A ◽  
Molecular Mechanisms ◽  
Secretory Granules ◽  
Active Role ◽  
Subcellular Fractionation ◽  
Neuroendocrine Cells ◽  
Cortical Actin ◽  
Neuropeptide Secretion ◽  
Granule Membrane

Chromogranins are a family of acidic glycoproteins that play an active role in hormone and neuropeptide secretion through their crucial role in secretory granule biogenesis in neuroendocrine cells. However, the molecular mechanisms underlying their granulogenic activity are still not fully understood. Because we previously demonstrated that the expression of the major component of secretory granules, chromogranin A (CgA), is able to induce the formation of secretory granules in nonendocrine COS-7 cells, we decided to use this model to dissect the mechanisms triggered by CgA leading to the biogenesis and trafficking of such granules. Using quantitative live cell imaging, we first show that CgA-induced organelles exhibit a Ca2+-dependent trafficking, in contrast to native vesicle stomatitis virus G protein-containing constitutive vesicles. To identify the proteins that confer such properties to the newly formed granules, we developed CgA-stably-expressing COS-7 cells, purified their CgA-containing granules by subcellular fractionation, and analyzed the granule proteome by liquid chromatography-tandem mass spectrometry. This analysis revealed the association of several cytosolic proteins to the granule membrane, including GTPases, cytoskeleton-based molecular motors, and other proteins with actin- and/or Ca2+-binding properties. Furthermore, disruption of cytoskeleton affects not only the distribution and the transport but also the Ca2+-evoked exocytosis of the CgA-containing granules, indicating that these granules interact with microtubules and cortical actin for the regulated release of their content. These data demonstrate for the first time that the neuroendocrine factor CgA induces the recruitment of cytoskeleton-, GTP-, and Ca2+-binding proteins in constitutively secreting COS-7 cells to generate vesicles endowed with typical dynamics and exocytotic properties of neuroendocrine secretory granules.

scholarly journals Regulated Exocytosis in Neuroendocrine Cells: A Role for Subplasmalemmal Cdc42/N-WASP-induced Actin Filaments

2004 ◽  
Vol 15 (2) ◽  
pp. 520-531 ◽  
Author(s):  
Stéphane Gasman ◽  
Sylvette Chasserot-Golaz ◽  
Magali Malacombe ◽  
Michael Way ◽  
Marie-France Bader
Keyword(s):  
Plasma Membrane ◽  
Membrane Trafficking ◽  
Actin Polymerization ◽  
Cell Activation ◽  
Secretory Granules ◽  
Small Gtpases ◽  
Neuroendocrine Cells ◽  
Actin Dynamics ◽  
Cell Periphery ◽  
Regulated Exocytosis

In neuroendocrine cells, actin reorganization is a prerequisite for regulated exocytosis. Small GTPases, Rho proteins, represent potential candidates coupling actin dynamics to membrane trafficking events. We previously reported that Cdc42 plays an active role in regulated exocytosis in chromaffin cells. The aim of the present work was to dissect the molecular effector pathway integrating Cdc42 to the actin architecture required for the secretory reaction in neuroendocrine cells. Using PC12 cells as a secretory model, we show that Cdc42 is activated at the plasma membrane during exocytosis. Expression of the constitutively active Cdc42L61 mutant increases the secretory response, recruits neural Wiskott-Aldrich syndrome protein (N-WASP), and enhances actin polymerization in the subplasmalemmal region. Moreover, expression of N-WASP stimulates secretion by a mechanism dependent on its ability to induce actin polymerization at the cell periphery. Finally, we observed that actin-related protein-2/3 (Arp2/3) is associated with secretory granules and that it accompanies granules to the docking sites at the plasma membrane upon cell activation. Our results demonstrate for the first time that secretagogue-evoked stimulation induces the sequential ordering of Cdc42, N-WASP, and Arp2/3 at the interface between granules and the plasma membrane, thereby providing an actin structure that makes the exocytotic machinery more efficient.

scholarly journals A Novel Site of Action for α-SNAP in the SNARE Conformational Cycle Controlling Membrane Fusion

2008 ◽  
Vol 19 (3) ◽  
pp. 776-784 ◽  
Author(s):  
Marcin Barszczewski ◽  
John J. Chua ◽  
Alexander Stein ◽  
Ulrike Winter ◽  
Rainer Heintzmann ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Plasma Membranes ◽  
Secretory Granules ◽  
Neuroendocrine Cells ◽  
Snare Complex ◽  
Protein Receptor ◽  
Sensitive Factor ◽  
Site Of Action ◽  
Snare Motif ◽  
Liposome Fusion

Regulated exocytosis in neurons and neuroendocrine cells requires the formation of a stable soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex consisting of synaptobrevin-2/vesicle-associated membrane protein 2, synaptosome-associated protein of 25 kDa (SNAP-25), and syntaxin 1. This complex is subsequently disassembled by the concerted action of α-SNAP and the ATPases associated with different cellular activities-ATPase N-ethylmaleimide-sensitive factor (NSF). We report that NSF inhibition causes accumulation of α-SNAP in clusters on plasma membranes. Clustering is mediated by the binding of α-SNAP to uncomplexed syntaxin, because cleavage of syntaxin with botulinum neurotoxin C1 or competition by using antibodies against syntaxin SNARE motif abolishes clustering. Binding of α-SNAP potently inhibits Ca2+-dependent exocytosis of secretory granules and SNARE-mediated liposome fusion. Membrane clustering and inhibition of both exocytosis and liposome fusion are counteracted by NSF but not when an α-SNAP mutant defective in NSF activation is used. We conclude that α-SNAP inhibits exocytosis by binding to the syntaxin SNARE motif and in turn prevents SNARE assembly, revealing an unexpected site of action for α-SNAP in the SNARE cycle that drives exocytotic membrane fusion.

scholarly journals Synaptic transmission molecules and their role in the pathogenesis of allergic rhinitis

2022 ◽  
Vol 20 (4) ◽  
pp. 143-152
Author(s):  
A. V. Klimov ◽  
O. V. Kalyuzhin ◽  
V. V. Klimov ◽  
O. A. Naidina
Keyword(s):  
Allergic Rhinitis ◽  
Nervous System ◽  
Immune System ◽  
Synaptic Transmission ◽  
Tumor Cells ◽  
Immune Cells ◽  
Allergic Inflammation ◽  
Entire Body ◽  
Local Allergic Rhinitis ◽  
The Impact

Immune cells and molecules, as well as synaptic transmission molecules play a regulatory role in the communication pathways of the entire body when it is necessary to engage all body resources in the fight against infections or tumor cells wherever they appear. In potential allergy, the neuroimmune network controls allergen tolerance maintenance at both local and systemic levels.The review focuses on different neurotransmitters and our understanding of a balance and imbalance between the immune system and the nervous system in allergic inflammation, including allergic rhinitis. However, the pathogenesis of the two endotypes of rhinitis (conventional allergic rhinitis and local allergic rhinitis) and the impact of the neuroimmune network on it remain unresolved. 

scholarly journals GTP-Binding Proteins and Regulated Exocytosis

1999 ◽  
Vol 10 (3) ◽  
pp. 284-306 ◽  
Author(s):  
E.L. Watson
Keyword(s):  
Membrane Trafficking ◽  
Binding Proteins ◽  
Molecular Mechanisms ◽  
Secretory Granules ◽  
Vesicular Trafficking ◽  
Snare Complex ◽  
Secretory Vesicles ◽  
Regulated Exocytosis ◽  
Gtp Binding Proteins ◽  
Gtp Binding

Regulated exocytosis, which occurs in response to stimuli, is a two-step process involving the docking of secretory granules (SGs) at specific sites on the plasma membrane (PM), with subsequent fusion and release of granule contents. This process plays a crucial role in a number of tissues, including exocrine glands, chromaffin cells, platelets, and mast cells. Over the years, our understanding of the proteins involved in vesicular trafficking has increased dramatically. Evidence from genetic, biochemical, immunological, and functional assays supports a role for ras-like monomeric GTP-binding proteins (smgs) as well as heterotrimeric GTP-binding protein (G-protein) subunits in various steps of the vesicular trafficking pathway, including the transport of secretory vesicles to the PM. Data suggest that the function of GTP-binding proteins is likely related to their localization to specific cellular compartments. The presence of both G-proteins and smgs on secretory vesicles/granules implicates a role for these proteins in the final stages of exocytosis. Molecular mechanisms of exocytosis have been postulated, with the identification of a number of proteins that modify, regulate, and interact with GTP-binding proteins, and with the advent of approaches that assess the functional importance of GTP-binding proteins in downstream, exocytotic events. Further, insight into vesicle targeting and fusion has come from the characterization of a SNAP receptor (SNARE) complex composed of vesicle, PM, and soluble membrane trafficking components, and identification of a functional linkage between GTP-binding and SNARES.

scholarly journals Protein p38: an integral membrane protein specific for small vesicles of neurons and neuroendocrine cells.

1986 ◽  
Vol 103 (6) ◽  
pp. 2511-2527 ◽  
Author(s):  
F Navone ◽  
R Jahn ◽  
G Di Gioia ◽  
H Stukenbrok ◽  
P Greengard ◽  
...  
Keyword(s):  
Nervous System ◽  
Membrane Protein ◽  
Synaptic Vesicles ◽  
Secretory Granules ◽  
Light And Electron Microscopy ◽  
Immunoblot Analysis ◽  
Integral Membrane Protein ◽  
Neuroendocrine Cells ◽  
Synapsin I ◽  
Large Dense Core Vesicles

An intrinsic membrane protein of brain synaptic vesicles with Mr 38,000 (p38, synaptophysin) has recently been partially characterized (Jahn, R., W. Schiebler, C. Ouimet, and P. Greengard, 1985, Proc. Natl. Acad. Sci. USA, 83:4137-4141; Wiedenmann, B., and W. W. Franke, 1985, Cell, 41:1017-1028). We have now studied the presence of p38 in a variety of tissues by light and electron microscopy immunocytochemistry and by immunochemistry. Our results indicate that, within the nervous system, p38, like the neuron-specific phosphoprotein synapsin I, is present in virtually all nerve terminals and is selectively associated with small synaptic vesicles (SSVs). No p38 was detectable on large dense-core vesicles (LDCVs). p38 and synapsin I were found to be present in similar concentrations throughout the brain. Outside the nervous system, p38 was found in a variety of neuroendocrine cells, but not in any other cell type. In neuroendocrine cells p38 was localized on a pleiomorphic population of small, smooth-surfaced vesicles, which were interspersed among secretory granules and concentrated in the Golgi area, but not on the secretory granules themselves. Immunoblot analysis of endocrine tissues and cell lines revealed a band with a mobility slightly different from that of neuronal p38. This difference was attributable to a difference in glycosylation. The finding that p38, like synapsin I, is a component of SSVs of virtually all neurons, but not of LDCVs, supports the idea that SSVs and LDCVs are organelles of two distinct pathways for regulated neuronal secretion. In addition, our results indicate the presence in a variety of neuroendocrine cells of an endomembrane system, which is related to SSVs of neurons but is distinct from secretory granules.

A gain-of-function mutant of Munc18-1 stimulates secretory granule recruitment and exocytosis and reveals a direct interaction of Munc18-1 with Rab3

2007 ◽  
Vol 409 (2) ◽  
pp. 407-416 ◽  
Author(s):  
Margaret E. Graham ◽  
Mark T. W. Handley ◽  
Jeff W. Barclay ◽  
Leo F. Ciufo ◽  
Stephanie L. Barrow ◽  
...  
Keyword(s):  
Pc12 Cells ◽  
Secretory Granules ◽  
Direct Interaction ◽  
Neuroendocrine Cells ◽  
Gain Of Function ◽  
Vesicle Docking ◽  
Pheochromocytoma Cells ◽  
Protein Receptor ◽  
Adrenal Chromaffin ◽  
Modes Of Interaction

Munc18-1 plays a crucial role in regulated exocytosis in neurons and neuroendocrine cells through modulation of vesicle docking and membrane fusion. The molecular basis for Munc18 function is still unclear, as are the links with Rabs and SNARE [SNAP (soluble N-ethylmaleimide-sensitive factor-attachment protein) receptor] proteins that are also required. Munc18-1 can bind to SNAREs through at least three modes of interaction, including binding to the closed conformation of syntaxin 1. Using a gain-of-function mutant of Munc18-1 (E466K), which is based on a mutation in the related yeast protein Sly1p, we have identified a direct interaction of Munc18-1 with Rab3A, which is increased by the mutation. Expression of Munc18-1 with the E466K mutation increased exocytosis in adrenal chromaffin cells and PC12 cells (pheochromocytoma cells) and was found to increase the density of secretory granules at the periphery of PC12 cells, suggesting a stimulatory effect on granule recruitment through docking or tethering. Both the increase in exocytosis and changes in granule distribution appear to require Munc18-1 E466K binding to the closed form of syntaxin 1, suggesting a role for this interaction in bridging Rab- and SNARE-mediated events in exocytosis.

scholarly journals Kalirin/Trio Rho Guanine Nucleotide Exchange Factors Regulate a Novel Step in Secretory Granule Maturation

2007 ◽  
Vol 18 (12) ◽  
pp. 4813-4825 ◽  
Author(s):  
Francesco Ferraro ◽  
Xin-Ming Ma ◽  
Jacqueline A. Sobota ◽  
Betty A. Eipper ◽  
Richard E. Mains
Keyword(s):  
Secretory Granule ◽  
Molecular Mechanisms ◽  
Secretory Granules ◽  
Guanine Nucleotide Exchange Factors ◽  
Neuroendocrine Cells ◽  
Secretory Cells ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors

The molecular mechanisms involved in the maturation of secretory granules, organelles that store hormones and neuropeptides, are poorly understood. As granule content proteins are processed, the composition of granule membranes changes, yielding constitutive-like secretion of immature content proteins and producing secretagogue-responsive mature granules. Constitutive-like secretion was not previously recognized as a process subject to regulation. We show that Kalirin and Trio, homologous Rho guanine nucleotide exchange factors (GEFs), which interact with a secretory granule resident protein, modulate cargo secretion from immature granules. Some of the Kalirin and Trio isoforms expressed in neuroendocrine cells colocalize with immature granules. Overexpression of their N-terminal GEF domain (GEF1) enhances secretion from immature granules, depleting cells of secretory cargo in the absence of secretagogue. This response requires GEF1 activity and is mimicked by Kalirin/Trio substrates Rac1 and RhoG. Accordingly, selective pharmacological inhibition of endogenous GEF1 activity decreases secretagogue-independent release of hormone precursors, accumulating product peptide in mature secretory granules. Kalirin/Trio modulation of cargo secretion from immature granules provides secretory cells with an extra layer of control over the sets of peptides released. Control of this step enhances the range of physiological responses that can be elicited, whereas lack of control could have pathological consequences.

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