Calcium Triggered Synaptic Vesicle Exocytosis

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dc.contributor.advisor Sudhof , Thomas C . en
dc.creator Pang , Zhiping en
dc.date.accessioned 2010 -07 -12T18 :42 :42Z en
dc.date.accessioned 2014 -02 -19T21 :59 :57Z
dc.date.available 2010 -07 -12T18 :42 :42Z en
dc.date.available 2014 -02 -19T21 :59 :57Z
dc.date.issued 2007 -08 -08 en
dc.identifier.other en
dc.identifier.uri http : / /hdl .handle .net /2152 .5 /643 en
dc.description.abstract Neurotransmitter release is triggered by the action potential induced influx of Ca 2+ into nerve terminals . One of the central questions in neuroscience is how Ca 2+ promotes synaptic vesicles from rest to fusion leading to release of neurotransmitters . In this thesis , I first addressed if synaptogmin -1 /SNARE binding is important for synaptic vesicle release . Using two knock -in mouse lines each with single amino -acid substitution , namely D232N and D238N in synaptotagmin -1 , combined with electrophysiology , I found evoked release in D232N mutant neuronal cultures is significantly increased , whereas in D238N cultures release is slightly but significantly decreased . Ca 2+ titration curves indicated the apparent Ca 2+ -affinity for vesicle release significantly increased in D232N synapses . These data are consistent with biochemical studies that showed that the D232N substitution in synaptotagmin -1 increases Ca 2+ -dependent SNARE bindings but leaves phospholipid binding unchanged , whereas the D238N mutant slightly decreased phospholipid binding but leaves SNARE binding insignificantly changed . Second , I addressed if synaptotamgin -2 is another Ca 2+ -sensor for synaptic vesicle release . I and my colleagues used two mouse lines : one contains a single amino acid mutation in synaptotagmin -2 (I377N ) and one has synaptotagmin -2 ablated from the genome . By using a combination of biophysical , biochemical and functional techniques , we determined that synaptotagmin -2 is a fast synchronous Ca 2+ -sensor . Third , in collaboration with Jianyuan Sun , we explored the biophysical properties of the slow Ca 2+ -sensor in the Calyx of Held . Using Ca 2+ -uncaging combined with electrophysiology , we mapped increasing Ca 2+ concentrations in relation to neurotransmitter release and built a comprehensive mathematical model for the Ca 2+ control of synaptic vesicle fusion . We found compelling evidence for the existence of two Ca 2+ - sensors : one (synaptotagmin -2 in the Calyx of Held ) is responsible for fast synchronous release , and the other one is responsible for slow delayed synaptic release . Surprisingly , we found the two Ca 2+ -sensors have similar apparent Ca 2+ affinities . This study showed clearly that synaptotagmin -2 is a fast Ca 2+ -sensor , and gave us a prediction that narrows down the potential candidate for the slow Ca 2+ -sensor . en
dc.format.medium Electronic en
dc.format.mimetype application /pdf en
dc.language.iso en en
dc.subject Calcium en
dc.subject Synapses en
dc.subject Synaptic Transmission en
dc.title Calcium Triggered Synaptic Vesicle Exocytosis en
dc.type.genre dissertation en
dc.type.material Text en
thesis.degree.name Doctor of Philosophy en
thesis.degree.level Ph .D . en
thesis.degree.discipline Neuroscience en
thesis.degree.grantor Graduate School of Biomedical Sciences en
thesis.degree.department en
dc.format.digitalOrigin born digital en
thesis.date.available 2007 -08 -08 en

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Calcium Triggered Synaptic Vesicle Exocytosis. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /643 .

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