Regulation of SNARE-Mediated Synaptic Vesicle Release by Synaptotagmins and Complexins

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dc.contributor.advisorSüdhof, Thomas C.en
dc.creatorKaeser-Woo, Yea Jinen
dc.date.accessioned2010-11-02T18:13:03Z
dc.date.available2010-11-02T18:13:03Z
dc.date.issued2010-11-02
dc.description.abstractIn the brain, neurons communicate with each other by synaptic transmission. This process includes release of neurotransmitter from vesicles in the presynaptic neuron into the synaptic cleft, and sensing of these neurotransmitters by the postsynaptic neuron with specific receptors. Long-lasting changes in the strength of synaptic contacts between neurons in the human brain, a process that is referred to as long-term synaptic plasticity, are the cellular correlates that underlie learning and memory. Synaptic transmission is initiated when an action potential arrives at the presynaptic terminal, and induces Ca2+ influx through voltage-gated Ca2+ channels. The SNARE (Soluble N-ethylmaleimide-sensitive-factor Attachment Protein Receptors) complex is the core component of the fusion machinery in the presynaptic terminal, as it forms a physical bridge between the vesicular membrane and the presynaptic target membrane that delivers the force to fuse the two membranes. Additional presynaptic proteins are required to activate or suppress neurotransmitter release which allows the presynaptic neuron to tightly control and regulate the process of neurotransmitter release. Among these proteins are synaptotagmins and complexins, two protein families that directly interact with the SNARE complex, and that are interdependent to each other in regulating SNARE-mediated synaptic vesicle release: complexin clamps neurotransmitter release until synaptotagmin is recruited by Ca2+ influx, and then it activates SNARE-mediated fusion process together with synaptotagmin. Here I describe the prospective in vivo function of synaptotagmin 12, a novel isoform of synaptotagmin, which lacks the typical Ca2+ binding residues of synaptotagmin, but instead contains a unique sequence motif which can be phosphorylated by cAMP-dependent protein kinase A. By using gene targeting method, I directly examined whether phosphorylation of synaptotagmin 12 is involved in presynaptic forms of long-term plasticity. In parallel, I developed a structure-function approach to functionally dissect how individual domains of complexin contribute to its dichotomic functions of clamping and activating neurotransmitter release. With this approach, we focused on how the accessory alpha-helix of complexin participates in SNARE-mediated synaptic fusion.en
dc.identifier.oclc742688765
dc.identifier.urihttps://hdl.handle.net/2152.5/806
dc.language.isoenen
dc.subjectSynaptic Transmissionen
dc.subjectCalcium Signalingen
dc.subjectSNARE Proteinsen
dc.titleRegulation of SNARE-Mediated Synaptic Vesicle Release by Synaptotagmins and Complexinsen
dc.typeThesisen
dc.type.materialTexten
thesis.date.available2012-09-20
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineNeuroscienceen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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