Identification of a Munc13-sensitive step in chromaffin cell large dense-core vesicle exocytosis

Man, Kwun Nok Mimi; Imig, Cordelia; Walter, Alexander; Pinheiro, Paulo S.; Stevens, David R.; Rettig, Jens; Sørensen, Jakob B.; Cooper, Benjamin H.; Brose, Nils; Wojcik, Sonja M.

doi:10.7554/elife.10635

Cited by 52 publications

(88 citation statements)

References 88 publications

(164 reference statements)

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“…), and indeed, the mechanism of docking appears to differ fundamentally between neuroendocrine cells and synapses (Man et al . ). Molecularly, syt‐1 appears to dock vesicles to negative charges on SNAP‐25 (Mohrmann et al .…”

Section: Synaptotagminmentioning

confidence: 97%

“…; Man et al . ). Mathematical modeling points to a kinetic difference in calcium‐dependent vesicle priming as causative, although the steady‐state calcium dependence of priming itself is the same (Man et al .…”

Section: Unc13/munc13 and Caps Proteinsmentioning

confidence: 97%

“…Mathematical modeling points to a kinetic difference in calcium‐dependent vesicle priming as causative, although the steady‐state calcium dependence of priming itself is the same (Man et al . ). Therefore, it is possible that calcium bind to Munc13‐1 and Munc13‐2 with the same affinities, or else that calcium bind to another protein, and the two Munc13 isoforms impart different kinetics of priming.…”

Section: Unc13/munc13 and Caps Proteinsmentioning

confidence: 97%

“…), which acts upstream of CAPS (Man et al . ). In spite of the presence of a C2‐domain in CAPS, calcium‐dependent functions have not been described (Martin ), possibly because the affinity for calcium is too low (Ann et al .…”

Section: Unc13/munc13 and Caps Proteinsmentioning

confidence: 97%

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C2‐domain containing calcium sensors in neuroendocrine secretion

Pinheiro

Houy

Sørensen

2016

Journal of Neurochemistry

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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. Keywords: calcium sensor, exocytosis, Munc13, neuroendocrine, synaptic transmission, synaptotagmin. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases". Cellular processes as distinct as neurotransmitter release, mast cell degranulation, and hormone release are brought about by calcium-dependent exocytosis (Lindau and Gomperts 1991;Bean et al. 1994;Sudhof 2013). Extensive research over several decades has elucidated the general mechanism behind those processes, and the functions of the key players involved. It is now clearly established that, both in synaptic and endocrine secretion, the vesicle fusion machinery is composed, at its core, by a set of proteins forming the soluble N-ethylmaleimide sensitive factor attachment receptor (SNARE) complex. The canonical (neuronal) SNARE complex consists of the vesicular SNARE protein synaptobrevin 2/VAMP-2 and the plasma membrane SNAREs synaptosomal-associated protein of 25 kDa (SNAP-25) and syntaxin-1 (Sollner et al. 1993). The~65-residue heptad-repeat SNARE motifs of these proteins form a parallel four-stranded helix bundle (Hanson et al. 1997;Sutton et al. 1998) that can zipper-up from its Nto C-terminus (Hua and Charlton 1999;Sorensen et al. 2006) in a stepwise manner (Gao et al. 2012;Min et al. 2013) to bring the two opposing membranes together. The formation of this trans alpha-helical ternary complex...

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Section: Synaptotagminmentioning

confidence: 97%

Section: Unc13/munc13 and Caps Proteinsmentioning

confidence: 97%

Section: Unc13/munc13 and Caps Proteinsmentioning

confidence: 97%

Section: Unc13/munc13 and Caps Proteinsmentioning

confidence: 97%

See 2 more Smart Citations

C2‐domain containing calcium sensors in neuroendocrine secretion

Pinheiro

Houy

Sørensen

2016

Journal of Neurochemistry

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“…On the other hand, Munc13-4 is involved in regulated exocytosis in hematopoietic secretory cells, such as cytotoxic T lymphocytes (CTLs), platelets, neutrophils, and mast cells (7,12,27,30,33,35). It is also known that in neurons, chromaffin cells, and CTLs, multiple Munc13 isoforms are endogenously expressed, and play some redundant roles in the promotion of the docking and priming of secretory vesicles/granules (8,10,24,36). In mast cells, Munc13-4 is shown to be crucial for degranulation (11,35,38); however, the involvement of other Munc13 isoform(s) still remains unknown.…”

Section: Rt-pcr and Quantitative Real-time Rt-pcrmentioning

confidence: 99%

<b>Inhibitory role of Munc13-1 in antigen-induced mast cell </b><b>degranulation </b>

2017

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Secretory granules (SGs) of mast cells are lysosome-related organelles that contain various inflammatory molecules such as histamine, which are stored in the cytoplasm. Mast cell degranulation is the regulated exocytosis of SGs in response to external stimuli, such as the antigen-mediated cross-linking of the high-affinity IgE receptor, FcεRI. Upon stimulation, SGs undergo priming to become fusion-competent prior to fusing with the plasma membrane, which is mediated by Munc13-4, one of the five members of the vesicle-priming Munc13 protein family. Although Munc13-4 is shown to be crucial for mast cell degranulation, the functional involvement of other Munc13 isoform(s) remains unknown. Herein, this was investigated using the RBL-2H3 mast cell line. We found that Munc13-1 and Munc13-4 are the only Munc13 isoforms that are expressed in the RBL-2H3 cells, and Munc13-1 is distributed in the cytoplasm, but highly concentrated on the late endosome and/or lysosome. Unexpectedly, antigen-induced degranulation was considerably increased by Munc13-1 knockdown, but decreased by its overexpression. Further, we found that the hypersecretion phenotype of the Munc13-1-knockdown cells was attenuated by simultaneous Munc13-4 knockdown. These results suggested that Munc13-1 has an inhibitory role in antigen-induced mast cell degranulation, which is performed in a Munc13-4-dependent manner.Mast cells are specialized secretory cells that play a central role in type I allergic reactions, as well as in certain innate and adaptive immune responses (1, 13). The antigen-mediated cross-linking of the highaffinity immunoglobulin E (IgE) receptor FcεRI triggers Ca 2+

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Neuronal SNARE complex assembly guided by Munc18‐1 and Munc13‐1

Wang

2022

FEBS Open Bio

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Neurotransmitter release by Ca2+‐triggered synaptic vesicle exocytosis is essential for information transmission in the nervous system. The soluble N‐ethylmaleimide sensitive factor attachment protein receptors (SNAREs) syntaxin‐1, SNAP‐25, and synaptobrevin‐2 form the SNARE complex to bring synaptic vesicles and the plasma membranes together and to catalyze membrane fusion. Munc18‐1 and Munc13‐1 regulate synaptic vesicle priming via orchestrating neuronal SNARE complex assembly. In this review, we summarize recent advances toward the functions and molecular mechanisms of Munc18‐1 and Munc13‐1 in guiding neuronal SNARE complex assembly, and discuss the functional similarities and differences between Munc18‐1 and Munc13‐1 in neurons and their homologs in other intracellular membrane trafficking systems.

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Identification of a Munc13-sensitive step in chromaffin cell large dense-core vesicle exocytosis

Cited by 52 publications

References 88 publications

C2‐domain containing calcium sensors in neuroendocrine secretion

C2‐domain containing calcium sensors in neuroendocrine secretion

<b>Inhibitory role of Munc13-1 in antigen-induced mast cell </b><b>degranulation </b>

Neuronal SNARE complex assembly guided by Munc18‐1 and Munc13‐1

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