Neurons and endocrine cells release signaling molecules by Ca2+?triggered exocytosis. Ca2+ enters a nerve terminal or endocrine cell, binds to a Ca2+ sensor protein on the vesicle membrane, and triggers the fusion of the vesicle membrane with the plasma membrane to expel some or all of the vesicle content into the extracellular space. To explore the mechanisms of this process our research focuses on the fusion pore, the initial aqueous passage between the vesicle interior and the outside of a cell. Studies of the fusion pore have given us valuable insights into the roles of specific molecules in the regulation of membrane fusion. The previous funding cycle saw progress in the identification of the vesicle protein synaptobrevin 2 as a fusion pore?forming protein in endocrine cells. This work revealed new unanticipated details in the structure of the fusion pore. We also showed that the transmembrane domain of this protein alters fusion pore stability by perturbing lipid bilayers. These findings raise new questions which we will attempt to answer by performing amperometry and capacitance recordings along with recordings of unitary synaptic current to obtain sensitive measures of fusion pore permeability and stability. We will build on insights from studies of endocrine fusion pores to test the role of the transmembrane domains of syntaxin and synaptobrevin in synaptic vesicle fusion pores. We will test the role of the vesicle protein synaptophysin in endocrine fusion pores by assaying flux and lipid perturbation. We will test the role of contacts between linkers and transmembrane domains of syntaxin and synaptobrevin in providing an energetic driving force for fusion pore expansion. These experiments will establish the specific functions of proteins associated with exocytosis. We will determine how these proteins contribute to the formation of specific structural intermediates of fusion, and how these proteins deform and remodel lipid bilayers to carry out these functions.

Public Health Relevance

Exocytosis is involved in virtually all forms of neuronal and endocrine signaling. A deeper understanding of the mechanisms of exocytosis will enable us to learn how the nervous system controls different forms of chemical signaling involved in information processing and normal neural function. These insights will help us understand how to treat medical problems involving impaired neural communication such as mental illness, learning disorders, epilepsy, and other neurological diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Leenders, Miriam
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Wisconsin Madison
Schools of Medicine
United States
Zip Code
Chiang, Chung-Wei; Chang, Che-Wei; Jackson, Meyer B (2018) The Transmembrane Domain of Synaptobrevin Influences Neurotransmitter Flux through Synaptic Fusion Pores. J Neurosci 38:7179-7191
Jackson, Meyer B (2017) Chemistry in a vesicle. J Gen Physiol 149:893-896
Chang, Che-Wei; Chiang, Chung-Wei; Jackson, Meyer B (2017) Fusion pores and their control of neurotransmitter and hormone release. J Gen Physiol 149:301-322
Chang, Che-Wei; Chiang, Chung-Wei; Gaffaney, Jon D et al. (2016) Lipid-anchored Synaptobrevin Provides Little or No Support for Exocytosis or Liposome Fusion. J Biol Chem 291:2848-57
McMahon, Shane M; Chang, Che-Wei; Jackson, Meyer B (2016) Multiple cytosolic calcium buffers in posterior pituitary nerve terminals. J Gen Physiol 147:243-54
Jackson, Meyer B (2016) The Hydrophobic Effect in Solute Partitioning and Interfacial Tension. Sci Rep 6:19265
Chang, Che-Wei; Jackson, Meyer B (2015) Synaptobrevin transmembrane domain influences exocytosis by perturbing vesicle membrane curvature. Biophys J 109:76-84
Chang, Che-Wei; Hui, Enfu; Bai, Jihong et al. (2015) A structural role for the synaptobrevin 2 transmembrane domain in dense-core vesicle fusion pores. J Neurosci 35:5772-80
McMahon, Shane M; Jackson, Meyer B (2014) In situ Ca2+ titration in the fluorometric study of intracellular Ca2+ binding. Cell Calcium 56:504-12
Yoo, Jejoong; Jackson, Meyer B; Cui, Qiang (2013) A comparison of coarse-grained and continuum models for membrane bending in lipid bilayer fusion pores. Biophys J 104:841-52

Showing the most recent 10 out of 31 publications