Synaptotagmins I and IV promote transmitter release independently of Ca2+ binding in the C2A domain

Robinson, Iain; Ranjan, Ravi; Schwarz, Thomas L.

doi:10.1038/nature00915

Cited by 218 publications

(170 citation statements)

References 31 publications

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“…5a). In agreement with previous studies (35)(36)(37) that demonstrate that Syts I and IV are functionally interchangeable, release was also recovered by expression of Syt I, but not by Syt V (Fig. 5b).…”

Section: Resultssupporting

confidence: 81%

Synaptotagmin IV regulates glial glutamate release

Zhang

Fukuda

Bockstaele

et al. 2004

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

193

168

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Calcium-binding synaptotagmins (Syts) are membrane proteins that are conserved from nematode to human. Fifteen Syts (Syts I-XV) have been identified in mammalian species. Syt I has been well studied and is a candidate for the Ca 2؉ -sensor that triggers evoked exocytosis underlying fast synaptic transmission. Whereas the functions of the other Syts are unclear, Syt IV is of particular interest because it is rapidly up-regulated after chronic depolarization or seizures, and because null mutations exhibit deficits in fine motor coordination and hippocampus-dependent memory. Screening Syts I-XIII, which are enriched in brain, we find that Syt IV is located in processes of astroglia in situ. Reduction of Syt IV in astrocytes by RNA interference decreases Ca 2؉ -dependent glutamate release, a gliotransmission pathway that regulates synaptic transmission. Mutants of the C2B domain, the only putative Ca 2؉ -binding domain in Syt IV, act in a dominant-negative fashion over Ca 2؉ -regulated glial glutamate release, but not gliotransmission induced by changes in osmolarity. Because we find that Syt IV is expressed predominantly by astrocytes and is not in the presynaptic terminals of the hippocampus, and because Syt IV knockout mice exhibit hippocampal-based memory deficits, our data raise the intriguing possibility that Syt IV-mediated gliotransmission contributes to hippocampal-based memory.

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Section: Resultssupporting

confidence: 81%

Synaptotagmin IV regulates glial glutamate release

Zhang

Fukuda

Bockstaele

et al. 2004

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

193

168

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“…46,47 Despite the lack of Ca 2+ binding by the Syt IV and Syt XI C2A domains, 46 Syt IV facilitates regulated exocytosis in neurons, astrocytes and endocrine cells. 28,[48][49][50] Similarly, Syt XI-containing vesicles undergo depolarization-triggered exocytosis in neurons. 42 Similar to neuronal lysosomes, 51 Syt XI-containing exocytic vesicles in neurons are acidic in nature and localize to dendrites.…”

Section: Discussionmentioning

confidence: 99%

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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“…Genetic knockouts of SYT1 result in dramatic suppression of evoked release in several model organisms (Bellen, 1999;Sudhof and Scheller, 2001). Of the two C2 domains, mutagenesis of C2B has a more severe effect on the SYT-controlled fast synchronous release (Fernandez-Chacon et al, 2001;Mackler et al, 2002;Robinson et al, 2002). In Drosophila melanogaster, a single mutation of tyrosine to asparagine in the C2B domain severely disrupts calcium-triggered exocytosis (Yoshihara and Littleton, 2002).…”

Section: Discussionmentioning

confidence: 99%

Conserved Prefusion Protein Assembly in Regulated Exocytosis

Rickman

Jiménez

Graham

et al. 2006

MBoC

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The regulated release of hormones and neurotransmitters is a fundamental process throughout the animal kingdom. The short time scale for the calcium triggering of vesicle fusion in regulated secretion suggests that the calcium sensor synaptotagmin and the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) membrane fusion machinery are well ordered before the calcium signal. To gain insight into the organization of the prefusion protein assembly in regulated exocytosis, we undertook a structural/functional study of the vesicular synaptotagmin1 and the plasma membrane SNARE proteins, which copurify from the brain in the absence of calcium. Based on an evolutionary analysis, mutagenesis screens, and a computational protein docking approach, we now provide the first testable description of the supramolecular prefusion assembly. Perturbing the determined synaptotagmin/SNARE-interacting interface in several models of regulated exocytosis altered the secretion of hormones and neurotransmitters. These mutations also disrupted the constitutive synaptotagmin/SNARE link in full agreement with our model. We conclude that the interaction of synaptotagmin with preassembled plasma membrane SNARE proteins, before the action of calcium, can provide a precisely organized "tethering" scaffold that underlies regulated secretion throughout evolution. INTRODUCTIONIn regulated secretion, fusion of docked secretory vesicles with the plasma membrane is triggered by the rapid elevation of the intracellular calcium concentration (Katz and Miledi, 1967). The membrane fusion itself is brought about by the action of the three soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, whereas the vesicular protein synaptotagmin (SYT) acts as the calcium sensor (Sollner et al., 1993;Sudhof and Scheller, 2001;Bonifacino and Glick, 2004). In neuroendocrine cells, the principal SNAREs are syntaxin1 and synaptosome-associated protein of 25 kDa (SNAP-25) on the plasma membrane (so-called target SNAREs or t-SNAREs), and vesicular synaptobrevin, also known as VAMP. Interaction between synaptobrevin and the two t-SNAREs leads to the formation of the ternary SNARE complex, a twisted parallel fourhelical bundle that probably drives membrane fusion (Sutton et al., 1998). With all the major players involved in vesicle fusion identified, it is becoming possible to tackle a central problem of this cellular process-how does calcium trigger vesicle fusion? Arguably, to understand the action of calcium it is essential to know 1) the extent of the assembly of the SNARE fusion proteins and 2) their organization in relation to the calcium sensor, SYT, before calcium-triggered events.It would be reasonable to assume that the SNAREs are at least partially preassembled, and the plasma membrane syntaxin and SNAP-25 are the first obvious candidates for being in such a ready state (An and Almers, 2004;Rickman et al., 2004b). Importantly, synaptobrevin binds syntaxin and SNAP-25 with high-affinity only when the two...

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Synaptotagmins I and IV promote transmitter release independently of Ca2+ binding in the C2A domain

Cited by 218 publications

References 31 publications

Synaptotagmin IV regulates glial glutamate release

Synaptotagmin IV regulates glial glutamate release

Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis

Conserved Prefusion Protein Assembly in Regulated Exocytosis

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