Medical College of Wisconsin
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Allosteric modulation of the presynaptic Ca2+ sensor for vesicle fusion. Nature 2005 May 26;435(7041):497-501

Date

05/27/2005

Pubmed ID

15917809

DOI

10.1038/nature03568

Scopus ID

2-s2.0-19444365446 (requires institutional sign-in at Scopus site)   234 Citations

Abstract

Neurotransmitter release is triggered by an increase in the cytosolic Ca2+ concentration ([Ca2+]i), but it is unknown whether the Ca2+-sensitivity of vesicle fusion is modulated during synaptic plasticity. We investigated whether the potentiation of neurotransmitter release by phorbol esters, which target presynaptic protein kinase C (PKC)/munc-13 signalling cascades, exerts a direct effect on the Ca2+-sensitivity of vesicle fusion. Using direct presynaptic Ca2+-manipulation and Ca2+ uncaging at a giant presynaptic terminal, the calyx of Held, we show that phorbol esters potentiate transmitter release by increasing the apparent Ca2+-sensitivity of vesicle fusion. Phorbol esters potentiate Ca2+-evoked release as well as the spontaneous release rate. We explain both effects by an increased fusion 'willingness' in a new allosteric model of Ca2+-activation of vesicle fusion. In agreement with an allosteric mechanism, we observe that the classically high Ca2+ cooperativity in triggering vesicle fusion (approximately 4) is gradually reduced below 3 microM [Ca2+]i, reaching a value of <1 at basal [Ca2+]i. Our data indicate that spontaneous transmitter release close to resting [Ca2+]i is a consequence of an intrinsic property of the molecular machinery that mediates synaptic vesicle fusion.

Author List

Lou X, Scheuss V, Schneggenburger R

Author

Xuelin Lou PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Allosteric Regulation
Animals
Brain Stem
Calcium
Calcium Signaling
Chromaffin Cells
Excitatory Postsynaptic Potentials
In Vitro Techniques
Membrane Fusion
Models, Biological
Neurotransmitter Agents
Phorbol 12,13-Dibutyrate
Presynaptic Terminals
Rats
Synapses
Synaptic Transmission