A dual-Ca2+-sensor model for neurotransmitter release in a central synapse

Sun, Jianyuan; Pang, Zhiping P.; Qin, Dengkui; Fahim, Abigail T.; Adachi, Roberto; Südhof, Thomas C.

doi:10.1038/nature06308

Cited by 333 publications

(571 citation statements)

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“…Members of the synaptotagmin (Syt) protein family that localize to vesicles function as Ca 2ϩ sensors that couple Ca 2ϩ rises to vesicle exocytosis (Chapman, 2002;Sudhof, 2004;Rizo et al, 2006). Syt-1 is the best understood isoform and functions as a synaptic vesicle Ca 2ϩ sensor for the rapid synchronous release (Geppert et al, 1994) but not for the slow asynchronous release of neurotransmitter (Sun et al, 2007) in hippocampal neurons. Syt-2 and -9 likely play similar roles at other synapses (Xu et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Synaptotagmin-1 Utilizes Membrane Bending and SNARE Binding to Drive Fusion Pore Expansion

Lynch

Gerona

Kielar

et al. 2008

MBoC

120

147

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In regulated vesicle exocytosis, SNARE protein complexes drive membrane fusion to connect the vesicle lumen with the extracellular space. The triggering of fusion pore formation by Ca 2؉ is mediated by specific isoforms of synaptotagmin (Syt), which employ both SNARE complex and membrane binding. Ca 2؉ also promotes fusion pore expansion and Syts have been implicated in this process but the mechanisms involved are unclear. We determined the role of Ca 2؉ -dependent Syt-effector interactions in fusion pore expansion by expressing Syt-1 mutants selectively altered in Ca 2؉ -dependent SNARE binding or in Ca 2؉ -dependent membrane insertion in PC12 cells that lack vesicle Syts. The release of differentsized fluorescent peptide-EGFP vesicle cargo or the vesicle capture of different-sized external fluorescent probes was used to assess the extent of fusion pore dilation. We found that PC12 cells expressing partial loss-of-function Syt-1 mutants impaired in Ca 2؉ -dependent SNARE binding exhibited reduced fusion pore opening probabilities and reduced fusion pore expansion. Cells with gain-of-function Syt-1 mutants for Ca 2؉ -dependent membrane insertion exhibited normal fusion pore opening probabilities but the fusion pores dilated extensively. The results indicate that Syt-1 uses both Ca 2؉ -dependent membrane insertion and SNARE binding to drive fusion pore expansion. INTRODUCTIONNeurotransmitter and peptide hormone secretion is mediated by the Ca 2ϩ -dependent exocytosis of vesicles at the plasma membrane. Vesicle fusion proceeds through membrane intermediates of stalk formation, fusion pore opening, and fusion pore expansion (Lindau and Alvarez de Toledo, 2003). In classical modes of vesicle exocytosis, fusion pores expand to the point where the vesicle membrane flattens on the plasma membrane (full fusion), leading to complete luminal contents release (full release). However, vesicle exocytosis can utilize alternative modes in which the fusion pore either abruptly closes (kiss-and-run) or in which the fusion pore dilates but subsequently recloses (cavicapture; Henkel and Almers, 1996). These transient modes of vesicle exocytosis lead to the partial release of luminal contents depending on the size and diffusibility of the cargo (Alvarez de Toledo et al., 1993;Barg et al., 2002;Taraska et al., 2003). Ca 2ϩ levels regulate fusion pore expansion as well as fusion pore formation (Fernandez-Chacon and Alvarez de Toledo, 1995;Hartmann and Lindau, 1995;Wang et al., 2006), but the mechanisms underlying fusion pore expansion, which is the more energetically demanding step, are poorly understood (Cohen and Melikyan, 2004).A Ca 2ϩ -dependent fusion machinery mediates the triggered formation of fusion pores. Three SNARE proteins (VAMP-2 on the vesicle with SNAP25 and syntaxin-1 on the plasma membrane) form trans complexes that promote close membrane apposition and membrane fusion (Weber et al., 1998). Members of the synaptotagmin (Syt) protein family that localize to vesicles function as Ca 2ϩ sensors that couple Ca 2ϩ rises ...

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Section: Introductionmentioning

confidence: 99%

Synaptotagmin-1 Utilizes Membrane Bending and SNARE Binding to Drive Fusion Pore Expansion

Lynch

Gerona

Kielar

et al. 2008

MBoC

120

147

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“…The in vivo study in his lab demonstrated that Syt1 knockout abolished the fast synchronous transmitter release and the mutation that changes the calcium affinity of endogenous Syt1 also altered the calcium-dependent synchronous neurotransmitter release to the same extent [3032]. These conclusions were reached based on the fact that the synaptotagmin knock-out/mutations caused neither impairment in calcium influx into the nerve terminal nor the disturbance of the spatial coupling between calcium channels and vesicles [32]. Furthermore, they found that only three synaptotagmins-Syt1, Syt2 and Syt9-mediate fast synaptic vesicle exocytosis.…”

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confidence: 81%

“…Only these isoforms of synaptotagmin were able to rescue the fast synchronous component of transmitter release in syt-1 deficient neurons [33]. All the results lead to the plausible mechanism that synaptotagmin functions as the calcium sensor and once calcium-binding sites of Synaptotagmin C 2 domain are occupied, the calcium-activated synaptotagmin interacts with SNARE complex, thereby triggering synaptic vesicle fusion [32].…”

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confidence: 86%

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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“…PTP in wild-type mice is similar to that observed in rats ( Figure 6E, left). In synaptotagmin-II knockout mice, however, EPSC and mEPSC potentiation disappeared following stimulation, which strongly suggests that synaptotagmin-II is required for PTP [24,31] (Figure 6E, right). When EGTA was added to the extracellular solution to buffer calcium, PTP and mEPSC potentiation disappeared, further confirming the requirement of calcium [24] .…”

Section: Compound Vesicle Fusion and Bulk Endocytosismentioning

confidence: 98%

“…Furthermore, the mEPSC measured from the postsynaptic cells showed no large events, indicating a small quantal size ( Figure 6D, bottom). Synaptotagmin is an immediate calcium sensor that mediates calcium-dependent exocytosis, and in the calyx of Held, synaptotagmin-II mediates this rapid fusion event [31] . These results together suggest that, similarly to regular fusion events, compound fusion requires synaptotagmin.…”

Section: Compound Vesicle Fusion and Bulk Endocytosismentioning

confidence: 99%

Synaptic vesicle recycling at the calyx of Held

Xue

Mei

2011

Acta Pharmacol Sin

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Efficient endocytosis is crucial for maintaining synaptic transmission because of its role in retrieving constituent membrane and associated proteins. In the past three decades three modes of endocytosis have been proposed involving the central nervous system: clathrin-mediated endocytosis, kiss-and-run endocytosis and bulk endocytosis. These forms of endocytosis can be induced under different conditions, but their detailed molecular mechanisms and functions are largely unknown. Here, we review the existence and initiation of all three modes of endocytosis at a giant glutamatergic synapse, the calyx of Held. The possibility of direct electrophysiology recording in this synapse allows for accurate tracking of exocytosis and endocytosis via capacitance measurements. Future aims will be focused on identifying the molecules that undergo the different mechanisms of endocytosis and the conditions under which different forms of endocytosis predominate.

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A dual-Ca2+-sensor model for neurotransmitter release in a central synapse

Cited by 333 publications

References 45 publications

Synaptotagmin-1 Utilizes Membrane Bending and SNARE Binding to Drive Fusion Pore Expansion

Synaptotagmin-1 Utilizes Membrane Bending and SNARE Binding to Drive Fusion Pore Expansion

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

Synaptic vesicle recycling at the calyx of Held

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