Membrane proximal lysosomes are the major vesicles responsible for calcium-dependent exocytosis in nonsecretory cells

Jaiswal, Jyoti K.; Andrews, Norma W.; Simon, Sanford M.

doi:10.1083/jcb.200208154

Cited by 332 publications

(354 citation statements)

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“…Similar to other vesicles, 32,33 lysosomes can fuse partially, releasing a part of their luminal content, and their membrane does not merge with the plasma membrane. 29,34 However, the existence of partial exocytosis of astrocyte lysosomes has been contested. 11,20 Using FITC dextran to label the lysosome lumen, we found that astrocyte lysosomes can exocytose their contents partially (Figure 2c) or fully (Figure 2d).…”

Section: Resultsmentioning

confidence: 99%

“…Such a mode of action of Syt XI would recapitulate our recent finding with an unrelated C2 domain containing protein called dysferlin, which facilitated injury-triggered lysosome exocytosis by tethering lysosomes to the cell membrane. 31 As it is the cell membrane proximal lysosome that undergo Ca 2+ -triggered exocytosis, 34 docking lysosome to the cell membrane may be a critical regulatory step for Ca 2+ -triggered lysosomal exocytosis, defect in which compromises cell membrane repair. Another mechanism by which Syt XI may regulate lysosome exocytosis is through interaction with the Q-SNARE Vti1a.…”

Section: Discussionmentioning

confidence: 99%

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Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis

et al. 2015

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Astrocytes are known to facilitate repair following brain injury; however, little is known about how injured astrocytes repair themselves. Repair of cell membrane injury requires Ca 2+ -triggered vesicle exocytosis. In astrocytes, lysosomes are the main Ca 2+ -regulated exocytic vesicles. Here we show that astrocyte cell membrane injury results in a large and rapid calcium increase. This triggers robust lysosome exocytosis where the fusing lysosomes release all luminal contents and merge fully with the plasma membrane. In contrast to this, receptor stimulation produces a small sustained calcium increase, which is associated with partial release of the lysosomal luminal content, and the lysosome membrane does not merge into the plasma membrane. In most cells, lysosomes express the synaptotagmin (Syt) isoform Syt VII; however, this isoform is not present on astrocyte lysosomes and exogenous expression of Syt VII on lysosome inhibits their exocytosis. Deletion of one of the most abundant Syt isoform in astrocyte -Syt XI -suppresses astrocyte lysosome exocytosis. This identifies lysosome as Syt XI-regulated exocytic vesicle in astrocytes. Further, inhibition of lysosome exocytosis (by Syt XI depletion or Syt VII expression) prevents repair of injured astrocytes. These results identify the lysosomes and Syt XI as the sub-cellular and molecular regulators, respectively of astrocyte cell membrane repair.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis

et al. 2015

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“…By contrast, D-serine colocalized with the small vesicular marker, VAMP2 and, to a lesser degree, VAMP3, supporting the idea that the amino acid is stored in synaptic-like vesicles. However, the two synaptobrevins are also present in endosomal sorting and recycling systems, which may represent an alternative vesicular source for D-serine, because these structures are known to be involved in Ca 2ϩ -dependent exocytosis in both secretory and nonsecretory cells (40).…”

Section: Discussionmentioning

confidence: 99%

Glutamate receptor activation triggers a calcium-dependent and SNARE protein-dependent release of the gliotransmitter D-serine

Mothet

Pollegioni

Ouanounou

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

392

350

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The gliotransmitter D-serine is released upon (S)-␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid͞kainate and metabotropic glutamate receptor stimulation, but the mechanisms involved are unknown. Here, by using a highly sensitive bioassay to continuously monitor extracellular D-serine levels, we have investigated the pathways used in its release. We reveal that D-serine release is inhibited by removal of extracellular calcium and augmented by increasing extracellular calcium or after treatment with the Ca 2؉ ionophore A23187. Furthermore, release of the amino acid is considerably reduced after depletion of thapsigargin-sensitive intracellular Ca 2؉ stores or chelation of intracellular Ca 2؉ with 1,2-bis(2-aminophenoxy)ethane-N,N,N ,N -tetraacetate-acetoxymethyl ester. Interestingly, D-serine release also was markedly reduced by concanamycin A, a vacuolar-type H ؉ -ATPase inhibitor, indicating a role for the vesicular proton gradient in the transmitter storage͞release. In addition, agonist-evoked D-serine release was sensitive to tetanus neurotoxin. Finally, immunocytochemical and sucrose density gradient analysis revealed that a large fraction of D-serine colocalized with synaptobrevin͞VAMP2, suggesting that it is stored in VAMP2-bearing vesicles. In summary, our study reveals the cellular mechanisms subserving D-serine release and highlights the importance of the glial cell exocytotic pathway in influencing CNS levels of extracellular D-serine.glia ͉ synaptobrevin ͉ D-amino acid ͉ vesicles ͉ tetanus neurotoxin A strocytes play pivotal roles in synaptic transmission by controlling transmitter diffusion and concentration in the extracellular space (1) and also by back-signaling to neurons directly through the release of neuroactive substances (2). Although glutamate and ATP are the most recognized chemical transmitters that mediate astrocyte-neuron signaling (2), other cell-cell mediators also are involved in this pathway. D-Serine has recently been identified as a major gliotransmitter in the central nervous system that serves as an endogenous ligand for the glycine site of NMDA receptors (3-6).However, many aspects regarding D-serine release still need to be addressed. Although it has been suggested that astrocytes may release D-serine, through the reverse operation of a sodiumdependent transporter (7), the precise molecular mechanisms underlying D-serine release are currently unknown. To unravel the functional consequences of D-serine-mediated astrocyte-toneuron signaling, it is essential to shed light on the mechanisms controlling the gliotransmitter storage and release pathways.For this purpose, we have devised a previously undescribed bioassay to continuously monitor the release of D-serine from cultured glial cells. In this work, we show that astrocytes and C6 glioma cells synthesize and contain a large amount of D-serine that can be released upon glutamate receptor (GluR) stimulation. Moreover, our observations demonstrate that D-serine release, evoked by glutamatergic agonists, is linked to a [Ca 2ϩ...

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“…Cell surface targeting of P2X4Rs by lysosomes has recently been shown to involve the chemokine CC2 [68]. It is well established that injury to a cell induces lysosome exoctyosis [35,38,57,66]; thus, it is conceivable that cell damage resulting from injury to a nerve might mobilize P2X4Rs from lysosomes to the microglial cell surface.…”

Section: Introductionmentioning

confidence: 99%

P2X4 purinoceptor signaling in chronic pain

Trang

Salter

2012

Purinergic Signalling

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ATP, acting via P2 purinergic receptors, is a known mediator of inflammatory and neuropathic pain. There is increasing evidence that the ATP-gated P2X4 receptor (P2X4R) subtype is a locus through which activity of spinal microglia and peripheral macrophages instigate pain hypersensitivity caused by inflammation or by injury to a peripheral nerve. The present article highlights the recent advances in our understanding of microglia-neuron interactions in neuropathic pain by focusing on the signaling and regulation of the P2X4R. We will also develop a framework for understanding converging lines of evidence for involvement of P2X4Rs expressed on macrophages in peripheral inflammatory pain.

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Membrane proximal lysosomes are the major vesicles responsible for calcium-dependent exocytosis in nonsecretory cells

Cited by 332 publications

References 41 publications

Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis

Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis

Glutamate receptor activation triggers a calcium-dependent and SNARE protein-dependent release of the gliotransmitter D-serine

P2X4 purinoceptor signaling in chronic pain

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