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Allosteric modulation of the presynaptic Ca2+ sensor for vesicle fusion
Xuelin Lou1, Volker Scheuss, Ralf Schneggenburger
1AG Synaptische Dynamik und Modulation und Abt. Membranbiophysik, Max-Planck-Institut für biophysikalische Chemie, Am Fassberg 11, D-37077 Göttingen, Germany.
Phorbol esters enhance neurotransmitter release by increasing calcium sensitivity in vesicle fusion. This suggests spontaneous release stems from the fusion machinery
Area of Science:
- Neuroscience
- Molecular Biology
- Synaptic Plasticity
Background:
- Neurotransmitter release depends on cytosolic calcium.
- The effect of synaptic plasticity on calcium sensitivity of vesicle fusion is unclear.
Purpose of the Study:
- Investigate if phorbol esters, targeting protein kinase C (PKC)/munc-13 pathways, directly alter vesicle fusion calcium sensitivity.
- Determine the mechanism behind phorbol ester-mediated potentiation of neurotransmitter release.
Main Methods:
- Utilized direct presynaptic calcium manipulation and calcium uncaging.
- Experimented on a giant presynaptic terminal (calyx of Held).
- Developed a new allosteric model for calcium-activated vesicle fusion.
Main Results:
- Phorbol esters increase the apparent calcium sensitivity of vesicle fusion.
- Both calcium-evoked and spontaneous release rates are potentiated by phorbol esters.
- Calcium cooperativity of vesicle fusion decreases at lower calcium concentrations, approaching 1 at basal levels.
Conclusions:
- Phorbol esters potentiate neurotransmitter release by enhancing the calcium sensitivity of vesicle fusion.
- Spontaneous neurotransmitter release is an inherent property of the synaptic vesicle fusion machinery.
- An allosteric model explains the observed calcium dependence and potentiation effects.
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