1. AG Synaptische Dynamik und Modulation und Abt. Membranbiophysik, Max-Planck-Institut für biophysikalische Chemie, Am Fassberg 11, D-37077 Göttingen, Germany
2. †Present address: Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA

Correspondence to: Ralf Schneggenburger¹ Correspondence and requests for materials should be addressed to R.S. (Email: rschneg@gwdg.de).

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^{1, 2, 3}, which target presynaptic protein kinase C (PKC)/munc-13 signalling cascades^{4, 5, 6}, 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 ( 4) is gradually reduced below 3 M [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^{7, 8} that mediates synaptic vesicle fusion.

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