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Volumn 13, Issue 3, 2003, Pages 315-323

Is synaptotagmin the calcium sensor?

Author keywords

[No Author keywords available]

Indexed keywords

CALCIUM; LIPID; NEUROTRANSMITTER; SNARE PROTEIN; SYNAPTOTAGMIN; SYNAPTOTAGMIN I; UNCLASSIFIED DRUG;

EID: 0038383475     PISSN: 09594388     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-4388(03)00063-1     Document Type: Review
Times cited : (63)

References (53)
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    • 2+ binding in the C2A domain. Nature. 418:2002;336-340 Using transgenic Drosophila, this study is the first to demonstrate that mutations in a C2A calcium-binding residue do not result in a null synaptotagmin phenotype. The authors further demonstrate that synaptotagmin IV, an isoform with defective calcium-dependent lipid-binding via its C2A domain, can rescue release defects in synaptotagmin I null mutations.
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    • This is the first study to specifically analyze mutations of calcium-binding residues in the C2B domain of synaptotagmin using transgenic Drosophila. C2B domain mutants that disrupt calcium-dependent phospholipid binding by the C2B domain in vitro have a strong dominant-negative effect in vivo, blocking fusion at a post-docking step during neurotransmitter release.
    • 2+-binding motif of synaptotagmin is required for synaptic transmission in vivo. Nature. 418:2002;340-344 This is the first study to specifically analyze mutations of calcium-binding residues in the C2B domain of synaptotagmin using transgenic Drosophila. C2B domain mutants that disrupt calcium-dependent phospholipid binding by the C2B domain in vitro have a strong dominant-negative effect in vivo, blocking fusion at a post-docking step during neurotransmitter release.
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    • Synaptotagmin I functions as a calcium regulator of release probability
    • This study used knock-in mice to analyze the in vivo effects of a mutated arginine residue near the calcium binding loops of C2A; this mutation causes a twofold decrease in calcium-dependent lipid binding of the native protein. Knock-in animals containing the mutant synaptotagmin I show a twofold decrease in release probability as measured in cultured hippocampal neurons. The decrease in release probability is attributed to a decline in the calcium sensitivity of release, as the size of the readily releasable pool and the frequency of miniature EPSCs are unaltered.
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    • This study describes a new fluorescence photoinactivation technique to acutely disrupt synaptotagmin function at the larval neuromuscular junction in transgenic Drosophila. Acute inactivation was accomplished through illumination of a fluorescein derivative coupled to a tetracysteine motif engineered into the C terminus of synaptotagmin I. Physiological recordings done on illuminated animals mimicked defects observed in synaptotagmin loss-of-function mutants, including a large reduction in evoked release and a decrease in calcium cooperativity. Furthermore, the authors use temporally controlled inactivation paradigms to show that the disruption in release is not caused by docking or by endocytotic defects.
    • Marek K.W., Davis G.W. Transgenically encoded protein photoinactivation (FlAsH-FALI): acute inactivation of synaptotagmin I. Neuron. 36:2002;805-813 This study describes a new fluorescence photoinactivation technique to acutely disrupt synaptotagmin function at the larval neuromuscular junction in transgenic Drosophila. Acute inactivation was accomplished through illumination of a fluorescein derivative coupled to a tetracysteine motif engineered into the C terminus of synaptotagmin I. Physiological recordings done on illuminated animals mimicked defects observed in synaptotagmin loss-of-function mutants, including a large reduction in evoked release and a decrease in calcium cooperativity. Furthermore, the authors use temporally controlled inactivation paradigms to show that the disruption in release is not caused by docking or by endocytotic defects.
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    • A structure-function characterization of the in vivo role of calcium-dependent synaptotagmin/SNAP-25 interactions is described. The authors demonstrate that mutations of several aspartic acid residues (D179, D186, D193) in the C terminus of SNAP-25 disrupt the protein's interaction with synaptotagmin but have little effect on SNARE complex formation. Introduction of mutant SNAP-25 into PC12 cells lacking endogenous SNAP-25 results in only partial rescue of calcium-dependent secretion, suggesting synaptotagmin-SNAP-25 interactions function in large dense-core vesicle exocytosis.
    • 2+-triggered exocytosis. Neuron. 34:2002;599-611 A structure-function characterization of the in vivo role of calcium-dependent synaptotagmin/SNAP-25 interactions is described. The authors demonstrate that mutations of several aspartic acid residues (D179, D186, D193) in the C terminus of SNAP-25 disrupt the protein's interaction with synaptotagmin but have little effect on SNARE complex formation. Introduction of mutant SNAP-25 into PC12 cells lacking endogenous SNAP-25 results in only partial rescue of calcium-dependent secretion, suggesting synaptotagmin-SNAP-25 interactions function in large dense-core vesicle exocytosis.
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    • Synaptotagmin modulation of fusion pore kinetics in regulated exocytosis of dense-core vesicles
    • This study documents changes in the kinetics of the fusion-pore opening of dense-core vesicles in PC12 cells overexpressing synaptotagmin I or synaptotagmin IV. This is the first demonstration that varying the levels of synaptotagmins on dense-core vesicles can alter fusion-pore characteristics and suggests that synaptotagmins function at the final step in fusion. Overexpression of synaptotagmins I and IV had opposite effects on the pore lifetime, with synaptotagmin I functioning to stabilize fusion pores whereas synaptotagmin IV destabilized fusion pores and decreased the number of fusion events.
    • Wang C.T., Grishanin R., Earles C.A., Chang P.Y., Martin T.F., Chapman E.R., Jackson M.B. Synaptotagmin modulation of fusion pore kinetics in regulated exocytosis of dense-core vesicles. Science. 294:2001;1111-1115 This study documents changes in the kinetics of the fusion-pore opening of dense-core vesicles in PC12 cells overexpressing synaptotagmin I or synaptotagmin IV. This is the first demonstration that varying the levels of synaptotagmins on dense-core vesicles can alter fusion-pore characteristics and suggests that synaptotagmins function at the final step in fusion. Overexpression of synaptotagmins I and IV had opposite effects on the pore lifetime, with synaptotagmin I functioning to stabilize fusion pores whereas synaptotagmin IV destabilized fusion pores and decreased the number of fusion events.
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    • Mechanism of calcium-independent synaptotagmin binding to target SNAREs
    • In this study the authors demonstrate that native synaptotagmin can bind to the specific t-SNARE heterodimer of syntaxin and SNAP-25, even in the absence of calcium. Synaptotagmin binding requires both C2 domains and both t-SNAREs, as no calcium-dependent interaction was observed with syntaxin and SNAP-25 in isolation. The authors propose that synaptotagmin's interaction with the t-SNARE heterodimer may precede fusion and facilitate SNARE complex formation during the fusion reaction.
    • Rickman C., Davletov B. Mechanism of calcium-independent synaptotagmin binding to target SNAREs. J. Biol. Chem. 278:2003;5501-5504 In this study the authors demonstrate that native synaptotagmin can bind to the specific t-SNARE heterodimer of syntaxin and SNAP-25, even in the absence of calcium. Synaptotagmin binding requires both C2 domains and both t-SNAREs, as no calcium-dependent interaction was observed with syntaxin and SNAP-25 in isolation. The authors propose that synaptotagmin's interaction with the t-SNARE heterodimer may precede fusion and facilitate SNARE complex formation during the fusion reaction.
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    • 2+ binding site of the synaptotagmin 1 C2B domain triggers fast exocytosis without stimulating SNARE interactions
    • The authors demonstrate that strontium-dependent release (although less robust than calcium-triggered fusion) is impaired in synaptotagmin knockout mice. The authors use biochemical analysis to demonstrate that strontium promotes synaptotagmin-phospholipid interactions but not synaptotagmin-SNARE binding. The authors suggest that the fast phase of release induced by strontium is unlikely to require synaptotagmin-SNARE interactions.
    • 2+ binding site of the synaptotagmin 1 C2B domain triggers fast exocytosis without stimulating SNARE interactions. Neuron. 37:2003;99-108 The authors demonstrate that strontium-dependent release (although less robust than calcium-triggered fusion) is impaired in synaptotagmin knockout mice. The authors use biochemical analysis to demonstrate that strontium promotes synaptotagmin-phospholipid interactions but not synaptotagmin-SNARE binding. The authors suggest that the fast phase of release induced by strontium is unlikely to require synaptotagmin-SNARE interactions.
    • (2003) Neuron , vol.37 , pp. 99-108
    • Shin, O.H.1    Rhee, J.S.2    Tang, J.3    Sugita, S.4    Rosenmund, C.5    Sudhof, T.C.6


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.