Allosteric modulation of the presynaptic Ca2+ sensor for vesicle fusion

X Lou, V Scheuss, R Schneggenburger - Nature, 2005 - nature.com
X Lou, V Scheuss, R Schneggenburger
Nature, 2005nature.com
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 …
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 (∼ 4) is gradually reduced below 3 µM [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.
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