Cell biology of Ca2+-triggered exocytosis

Pang, Zhiping P.; Südhof, Thomas C.

doi:10.1016/j.ceb.2010.05.001

Cited by 341 publications

(305 citation statements)

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“…The action of SNARE is regulated by synaptotagmins (Syts), which are a large group of membrane proteins that regulate vesicle docking and fusion in processes such as the exocytosis of synaptic vesicles and hormones (19), phagocytosis (18,20), mast cell degranulation, and acrosome exocytosis in sperm cells (21). All Syts possess a single transmembrane domain, and two conserved tandem C2 domains, which were originally identified in protein kinase C (22).…”

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confidence: 99%

“…Eight members of the Syt family function as Ca 2+ sensors of vesicle fusion by virtue of the C2 domains present in these Syts. Syts IV and XI, however, belong to a different Syt family in which a conserved serine in the C2A domain precludes these Syts from binding Ca 2+ and phospholipids (19,23). In fact, murine Syts IV and XI inhibit vesicle fusion (24) and may mediate vesicle trafficking processes that do not depend on Ca 2+ (23,24).…”

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confidence: 99%

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Synaptotagmin XI Regulates Phagocytosis and Cytokine Secretion in Macrophages

Duque

Fukuda

Descoteaux

2013

The Journal of Immunology

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Synaptotagmins (Syts) are a group of type I membrane proteins that regulate vesicle docking and fusion in processes such as exocytosis and phagocytosis. All Syts possess a single transmembrane domain, and two conserved tandem Ca2+-binding C2 domains. However, Syts IV and XI possess a conserved serine in their C2A domain that precludes these Syts from binding Ca2+ and phospholipids, and from mediating vesicle fusion. Given the importance of vesicular trafficking in macrophages, we investigated the role of Syt XI in cytokine secretion and phagocytosis. We demonstrated that Syt XI is expressed in murine macrophages, localized in recycling endosomes, lysosomes, and recruited to phagosomes. Syt XI had a direct effect on phagocytosis and on the secretion of TNF and IL-6. Whereas small interfering RNA–mediated knockdown of Syt XI potentiated secretion of these cytokines and particle uptake, overexpression of an Syt XI construct suppressed these processes. In addition, Syt XI knockdown led to decreased recruitment of gp91phox and lysosomal-associated membrane protein–1 to phagosomes, suggesting attenuated microbicidal activity. Remarkably, knockdown of Syt XI ensued in enhanced bacterial survival. Our data reveal a novel role for Syt XI as a regulator of cytokine secretion, particle uptake, and macrophage microbicidal activity.

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Synaptotagmin XI Regulates Phagocytosis and Cytokine Secretion in Macrophages

Duque

Fukuda

Descoteaux

2013

The Journal of Immunology

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“…An exception is the ciliate, Paramecium, where a rapidly activated SOCE underlies the fastest known exocytosis of dense core-secretory vesicles important for predator defence [40,135]. The final target of Ca 2þ during any type of secretion is the C2-domain-bearing protein synaptotagmin, and closely related Ca 2þ -sensors, such as extended synaptotagmin isoforms of which several ( probably with different kinetics) are known [53].…”

Section: Intracellular Ca 2þ Fluxes and Ca 2þ Regulationmentioning

confidence: 99%

“…Gradual conformational changes can thus serve for the transmission of a chemical signal into a mechanical one, be it at a subunit of plasmalemmal ion channels in protozoa [51] or intracellular Ca 2þ -release channels in mammals [52]. The Ca 2þ -sensor for membrane fusion, synaptotagmin, possesses distinct C2 domains for cooperative Ca 2þ -binding [53]. These C2 domains stick out from b-barrel structures can flow into the cell by influx channels of different types.…”

Section: Some Evolutionary Preconditions and Basic Considerations Of mentioning

confidence: 99%

Inseparable tandem: evolution chooses ATP and Ca²⁺to control life, death and cellular signalling

Plattner

Verkhratsky

2016

Phil. Trans. R. Soc. B

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From the very dawn of biological evolution, ATP was selected as a multipurpose energy-storing molecule. Metabolism of ATP required intracellular free Ca 2þ to be set at exceedingly low concentrations, which in turn provided the background for the role of Ca 2þ as a universal signalling molecule. The early-eukaryote life forms also evolved functional compartmentalization and vesicle trafficking, which used Ca 2þ as a universal signalling ion; similarly, Ca 2þ is needed for regulation of ciliary and flagellar beat, amoeboid movement, intracellular transport, as well as of numerous metabolic processes. Thus, during evolution, exploitation of atmospheric oxygen and increasingly efficient ATP production via oxidative phosphorylation by bacterial endosymbionts were a first step for the emergence of complex eukaryotic cells. Simultaneously, Ca 2þ started to be exploited for shortrange signalling, despite restrictions by the preset phosphate-based energy metabolism, when both phosphates and Ca 2þ interfere with each other because of the low solubility of calcium phosphates. The need to keep cytosolic Ca 2þ low forced cells to restrict Ca 2þ signals in space and time and to develop energetically favourable Ca 2þ signalling and Ca 2þ microdomains. These steps in tandem dominated further evolution. The ATP molecule (often released by Ca 2þ -regulated exocytosis) rapidly grew to be the universal chemical messenger for intercellular communication; ATP effects are mediated by an extended family of purinoceptors often linked to Ca 2þ signalling. Similar to atmospheric oxygen, Ca 2þ must have been reverted from a deleterious agent to a most useful (intra-and extracellular) signalling molecule. Invention of intracellular trafficking further increased the role for Ca 2þ homeostasis that became critical for regulation of cell survival and cell death. Several mutually interdependent effects of Ca 2þ and ATP have been exploited in evolution, thus turning an originally unholy alliance into a fascinating success story.This article is part of the themed issue 'Evolution brings Ca 2þ and ATP together to control life and death'.

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“…The new discovery of biochemical properties of Syt1 lead Südhof to speculate that syt-1 and/or some other protein family members might be the long-sought calcium sensor(s) for neurotransmitter release [26]. He kept decades-long focus on the systematic study of synaptotagmin protein family thereafter [27]. He carried out a series of biochemical studies on interactions between syt-1 and an array of presynaptic proteins [28].…”

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A legend of the SNARE complex and synaptotagmin—the insight into synaptic transmission

Sun

2013

Sci. China Life Sci.

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Citation:Sun J Y. A legend of the SNARE complex and synaptotagmin-the insight into synaptic transmission. Sci China Life Sci, 2013Sci, , 56: 1150Sci, -1153Sci, , doi: 10.1007 The 2013 Nobel Prize in Physiology or Medicine honors three scientists, James Rothman, Randy Schekman and Thomas Südhof, whose work revealed the mystery of the vesicle trafficking, i.e., how cells, from yeast to mammals, organize their transport systems. In a neuroscience perspective, this decades-long story might be described as a legend of identifying the SNARE complex and synaptotagmin proteins, revealing their functional mechanisms, and shedding an insight into synaptic transmission. Their research unmasked the exquisitely precise control of synaptic vesicle fusion. Here I will only review the history of how their pioneer work on vesicle fusion machinery served as a major step forward in our understanding of neuronal signaling. Classical physiological studies revealed the central importance of synapses in brain function, indicating that neurons communicate between each other primarily by chemical transmission at the synapse. Synaptic function is crucial for the brain to mediate intelligence, feelings and behavior. Most neuronal and mental diseases such as schizophrenia, depression, bipolar disorder and many other pathological conditions attribute to synaptic defects. Through their discoveries, three scientists greatly advanced our understanding of neuronal information processing.However, it is not an overnight thing-as Rothman described their achievements-most of it has been accomplished and developed over many years, if not decades. Indeed, it is a legend with many trials and tribulations. This actually was a decades-long legend of a group of scientists who have extraordinary courage, determination, vision, and insight, in searching for this synaptic vesicle fusion machinery.In mid-1970s, the general picture drawn by the pioneers of cell biology was that cells bustle with transport activities, multiple types of small bubble-like organelles called vesicles ferry cellular substances from one site to another, possibly via well-designated targeting pathways [1]. Some vesicles that shuttle between organelles had been revealed and even mapped in the pathway of membrane budding or fusing [13]. In the neuroscience field, it was found that nerve cells (or neurons) communicate with each other through specialized contact points called synapses. The synapse allows a neuron to transmit an electrical or chemical signal to another cell. As early as 1951, Bernard Katz demonstrated that a chemical transmitter is released from a structure at the end of the neuron, called the presynaptic nerve terminal, to the outside of the neuron in a quantized fashion [4,5]. The quantum-like signal was later found to be due to the secretion of multiple neurotransmitter molecules from a packet organelle called the "synaptic vesicle" in the nerve terminal [1]. Bernard Katz's another finding was that neurotransmitter releasing is highly regulated in response to Ca ...

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Cell biology of Ca2+-triggered exocytosis

Cited by 341 publications

References 80 publications

Synaptotagmin XI Regulates Phagocytosis and Cytokine Secretion in Macrophages

Synaptotagmin XI Regulates Phagocytosis and Cytokine Secretion in Macrophages

Inseparable tandem: evolution chooses ATP and Ca²⁺to control life, death and cellular signalling

A legend of the SNARE complex and synaptotagmin—the insight into synaptic transmission

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Cell biology of Ca2+-triggered exocytosis

Cited by 341 publications

References 80 publications

Synaptotagmin XI Regulates Phagocytosis and Cytokine Secretion in Macrophages

Synaptotagmin XI Regulates Phagocytosis and Cytokine Secretion in Macrophages

Inseparable tandem: evolution chooses ATP and Ca2+to control life, death and cellular signalling

A legend of the SNARE complex and synaptotagmin—the insight into synaptic transmission

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Inseparable tandem: evolution chooses ATP and Ca²⁺to control life, death and cellular signalling