Allosteric modulation of the presynaptic Ca2+ sensor for vesicle fusion
Allosteric modulation of the presynaptic Ca2+ sensor for vesicle fusion
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DOI：
10.1038/nature03568
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发表时间：
2005-05-26
期刊：
影响因子：
64.8
通讯作者：
Schneggenburger, R
中科院分区：
文献类型：
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作者：
Lou, XL;Scheuss, V;Schneggenburger, R
神经递质的释放是由胞质Ca 2+浓度（[Ca 2 +]（i））的增加触发的，但尚不清楚囊泡融合的Ca 2+敏感性是否在突触可塑性过程中受到调节。我们研究了佛波醇酯（1-3）对神经递质释放的增强作用，其靶向突触前蛋白激酶C（PKC）/munc-13信号级联（4-6），是否对囊泡融合的Ca 2+敏感性产生直接影响。使用直接的突触前Ca 2+操纵和Ca 2 + uncaging在一个巨大的突触前终端，萼举行，我们表明，佛波酯增强发射器的释放，通过增加明显的Ca 2+敏感性囊泡融合。佛波酯增强Ca 2+诱发的释放以及自发释放速率。我们解释了这两种效果增加融合的“意愿”在一个新的变构模型的钙激活囊泡融合。与变构机制一致，我们观察到触发囊泡融合的经典高Ca 2+协同性（类似于4）在低于3 μ M [Ca 2 +]（i）时逐渐降低，在基础[Ca 2 +]（i）时达到< 1的值。我们的数据表明，接近静息[Ca 2 +]（i）的自发递质释放是介导突触囊泡融合的分子机制（7，8）的内在特性的结果。
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.