AG Optobiology, Institute of Biology, Humboldt Universität Zu Berlin, 10115, Berlin, Germany.
Guest Group, "Neuronal Protein Transport", Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany.
Cell Mol Life Sci. 2024 Aug 9;81(1):342. doi: 10.1007/s00018-024-05327-8.
A Disintegrin And Metalloproteinase 10 (ADAM10) plays a pivotal role in shaping neuronal networks by orchestrating the activity of numerous membrane proteins through the shedding of their extracellular domains. Despite its significance in the brain, the specific cellular localization of ADAM10 remains not well understood due to a lack of appropriate tools. Here, using a specific ADAM10 antibody suitable for immunostainings, we observed that ADAM10 is localized to presynapses and especially enriched at presynaptic vesicles of mossy fiber (MF)-CA3 synapses in the hippocampus. These synapses undergo pronounced frequency facilitation of neurotransmitter release, a process that play critical roles in information transfer and neural computation. We demonstrate, that in conditional ADAM10 knockout mice the ability of MF synapses to undergo this type of synaptic plasticity is greatly reduced. The loss of facilitation depends on the cytosolic domain of ADAM10 and association with the calcium sensor synaptotagmin 7 rather than ADAM10's proteolytic activity. Our findings unveil a new role of ADAM10 in the regulation of synaptic vesicle exocytosis.
解整合素金属蛋白酶 10（ADAM10）通过调控众多膜蛋白的活性来调控细胞外结构域的脱落，从而在塑造神经网络方面发挥着关键作用。尽管 ADAM10 在大脑中具有重要意义，但由于缺乏适当的工具，其特定的细胞定位仍未得到很好的理解。在这里，我们使用一种适合免疫染色的特异性 ADAM10 抗体，观察到 ADAM10 定位于突触前，并在海马体的苔藓纤维（MF）-CA3 突触的突触前囊泡中特别丰富。这些突触经历神经递质释放的明显频率易化，这一过程在信息传递和神经计算中起着关键作用。我们证明，在条件性 ADAM10 敲除小鼠中，MF 突触经历这种类型的突触可塑性的能力大大降低。这种易化的丧失取决于 ADAM10 的胞质结构域和与钙传感器突触结合蛋白 7 的关联，而不是 ADAM10 的蛋白水解活性。我们的发现揭示了 ADAM10 在调节突触囊泡胞吐作用中的新作用。
