衔接蛋白 AP-3 通过招募磷脂翻转酶 ATP8A1 产生高频释放的突触小泡。
Adaptor protein AP-3 produces synaptic vesicles that release at high frequency by recruiting phospholipid flippase ATP8A1.
机构信息
Departments of Physiology and Neurology, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
Department of Pharmaceutical Chemistry, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
出版信息
Nat Neurosci. 2023 Oct;26(10):1685-1700. doi: 10.1038/s41593-023-01434-0. Epub 2023 Sep 18.
Neural systems encode information in the frequency of action potentials, which is then decoded by synaptic transmission. However, the rapid, synchronous release of neurotransmitters depletes synaptic vesicles (SVs), limiting release at high firing rates. How then do synapses convey information about frequency? Here, we show in mouse hippocampal neurons and slices that the adaptor protein AP-3 makes a subset of SVs that respond specifically to high-frequency stimulation. Neurotransmitter transporters slot onto these SVs in different proportions, contributing to the distinct properties of release observed at different excitatory synapses. Proteomics reveals that AP-3 targets the phospholipid flippase ATP8A1 to SVs; loss of ATP8A1 recapitulates the defect in SV mobilization at high frequency observed with loss of AP-3. The mechanism involves recruitment of synapsin by the cytoplasmically oriented phosphatidylserine translocated by ATP8A1. Thus, ATP8A1 enables the subset of SVs made by AP-3 to release at high frequency.
神经系统通过动作电位的频率来编码信息，然后通过突触传递进行解码。然而，神经递质的快速、同步释放会耗尽突触小泡（SVs），从而限制了高频放电时的释放。那么，突触如何传递关于频率的信息呢？在这里，我们在小鼠海马神经元和切片中表明，衔接蛋白 AP-3 使一部分 SV 对高频刺激做出特异性反应。神经递质转运体以不同的比例插入这些 SV 中，有助于解释在不同兴奋性突触中观察到的释放特性的差异。蛋白质组学揭示了 AP-3 将磷脂翻转酶 ATP8A1 靶向 SV；ATP8A1 的缺失重现了 AP-3 缺失时高频刺激下 SV 动员的缺陷。该机制涉及由 ATP8A1 移位的质膜取向的磷脂酰丝氨酸募集突触结合蛋白。因此，ATP8A1 使 AP-3 产生的 SV 子集能够高频释放。
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