Augmenting neurotransmitter release by enhancing the apparent Ca2+ affinity of synaptotagmin 1
Augmenting neurotransmitter release by enhancing the apparent Ca2+ affinity of synaptotagmin 1
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DOI：
10.1073/pnas.0509153102
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发表时间：
2005-12-20
影响因子：
11.1
通讯作者：
Rosenmund, C
中科院分区：
文献类型：
--
作者：
Rhee, JS;Li, LY;Rosenmund, C
Synaptotagmin 1可能通过与其两个C2结构域的Ca2+结合而在神经递质释放中充当Ca2+传感器。这一观点得到了以下观察结果的有力支持：C2A结构域中的突变导致突触结合蛋白1的表观Ca 2+亲和力和释放的Ca 2+敏感性平行降低。然而，这项研究是基于一个单一的功能丧失突变。我们现在表明，色氨酸取代的synaptotagmin 1 C2结构域作为功能获得性突变，以增加表观Ca2+的亲和力synaptotagmin 1。同样的取代，当引入神经元中表达的突触结合蛋白1时，增强了释放的Ca 2+敏感性。两个C2结构域中的突变导致释放中的可比和累加效应。因此，我们的研究结果表明，释放的表观Ca2+的敏感性是由突触结合蛋白1在两个方向上的表观Ca2+亲和力决定的，并且Ca2+与两个C2结构域的结合有助于Ca2+触发释放。
Synaptotagmin 1 likely acts as a Ca2+ sensor in neurotransmitter release by Ca2+-binding to its two C2 domains. This notion was strongly supported by the observation that a mutation in the C2A domain causes parallel decreases in the apparent Ca2+ affinity of synaptotagmin 1 and in the Ca2+ sensitivity of release. However, this study was based on a single loss-of-function mutation. We now show that tryptophan substitutions in the synaptotagmin 1 C2 domains act as gain-of-function mutations to increase the apparent Ca2+ affinity of synaptotagmin 1. The same substitutions, when introduced into synaptotagmin 1 expressed in neurons, enhance the Ca2+ sensitivity of release. Mutations in the two C2 domains lead to comparable and additive effects in release. Our results thus show that the apparent Ca2+ sensitivity of release is dictated by the apparent Ca2+ affinity of synaptotagmin 1 in both directions, and that Ca2+ binding to both C2 domains contributes to Ca2+ triggering of release.