ADDUCIN REGULATES THE NEUROMUSCULAR JUNCTION IN DROSOPHILA

神经细胞通过称为突触的连接相互通信；当神经元连接到肌肉时，连接的突触称为神经肌肉连接(NMJ)。NMJ类似于神经元之间的突触，但不完全相同，通常可以作为突触的模型。我们发现，一种名为内收蛋白(ADD)的蛋白质位于果蝇的NMJ处。其他人发现，这种蛋白质存在于哺乳动物大脑的突触中。了解这种蛋白质在果蝇NMJ中的功能可以帮助我们了解大脑中的突触是如何工作的，这也可以澄清记忆和学习是如何发生的。我们还发现，内收蛋白的水平(在果蝇中称为HTS)可以增加或减少NMJ处突触分支的大小。这一点很重要，因为突触分支很可能参与修改“运动记忆”，或者可能作为一种改变从神经元到肌肉的信息传输效率的方式，从而提高运动表现的精确度。为了了解内收蛋白是如何实现其作用的，我们将看看它与哪些其他蛋白质相互作用。我们发现内收蛋白/HTS与另一种名为Discs Large(DLG)的蛋白质密切相关，DLG在结构上类似于哺乳动物突触中的一种重要蛋白质PSD-95蛋白。有趣的是，内收蛋白/HTS蛋白可以通过几种称为蛋白激酶的酶的作用来修饰DLG蛋白，我们认为ADD/HTS是通过这些蛋白激酶来修饰DLG的。在这项研究中，我们将探索内收蛋白/HTS的作用在多大程度上是通过作用于DLG来实现的。我们还将探索内收蛋白/HTS可能如何发挥作用的其他方式，即使其影响不是由DLG介导的。例如，内收蛋白/HTS可能附着在细胞膜上，并充当支架，允许结合对突触结构重要的肌动蛋白和血影蛋白细丝的细胞“骨架”。

Nerve cells communicate with one another at junctions termed synapses; when a neuron connects to muscle, the connecting synapse is called a neuromuscular junction (NMJ). The NMJ is similar but not identical to synapses between neurons and can can serve as a model for synapses in general. We have found that a protein called Adducin (Add) is located at the NMJ of the fruit fly. Others have found that this protein is present in synapses in the mammalian brain. Knowledge about the function of this protein at the fruit fly NMJ can help us understand how synapses in the brain work, which could also clarify how memory and learning occur. We have also found that levels of Adducin (called Hts in the fly) can increase or decrease the size of the synaptic branching at the NMJ. This is important as the synaptic branching is likely involved in modifying a 'motor memory', or may serve as a way of changing the efficiency of information transfer from a neuron to a muscle so as to enhance motor performance precision. To understand how Adducin achieves its effects we will see what other proteins it interacts with. We find that Adducin/Hts is closely linked to another protein called Discs large (Dlg), which is similar in structure to an important protein in mammalian synapses called the PSD-95 protein. Interestingly, the Adducin/Hts protein can modify the Dlg protein through the action of several enzymes called protein kinases and we think that Add/Hts is acting through these protein kinases to modify Dlg. In this grant we will explore how much of the effects of Adducin/Hts is mediated by acting on Dlg. We will also explore other ways of how Adducin/Hts may be acting even if its effects are not mediated by Dlg. For instance, Adducin/Hts may be sticking to the membranes of cells and acting as a scaffold to permit binding of the cellular 'skeleton' of actin and spectrin filaments that are important for the structure of the synapse.