Allosteric modulation of the presynaptic Ca2+ sensor for vesicle fusion

Article

关键词: PROTEIN-KINASE-C;    TRANSMITTER RELEASE;    CALCIUM SENSITIVITY;    CHROMAFFIN CELLS;    MEMBRANE-FUSION;    PHORBOL ESTERS;    POTENTIATION;    POOL;    NEUROTRANSMITTER;    AUGMENTATION;   

DOI  :  10.1038/nature03568

来源: SCIE

【 摘 要 】

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(1-3), which target presynaptic protein kinase C (PKC)/munc-13 signalling cascades(4-6), 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 (similar to 4) is gradually reduced below 3 mu 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.

【 授权许可】

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