ADDUCIN REGULATES THE NEUROMUSCULAR JUNCTION IN DROSOPHILA

神经细胞在称为突触的连接处相互交流；当神经元与肌肉连接时，这种连接突触被称为神经肌肉连接（NMJ）。NMJ与神经元之间的突触相似但不完全相同，可以作为一般突触的模型。我们发现一种叫做内收蛋白（Add）的蛋白质位于果蝇的NMJ。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理解大脑中的突触是如何工作的，这也可以解释记忆和学习是如何发生的。我们还发现内收蛋白（在果蝇中称为Hts）的水平可以增加或减少NMJ突触分支的大小。这是很重要的，因为突触分支可能涉及修改“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递效率的方式，从而提高运动表现的精度。为了理解内收蛋白是如何达到效果的，我们将看看它与其他蛋白质相互作用。我们发现内收蛋白/Hts与另一种名为disc large （Dlg）的蛋白紧密相连，该蛋白在结构上与哺乳动物突触中的一种重要蛋白PSD-95蛋白相似。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。在本研究中，我们将探讨内收蛋白/Hts的作用有多少是通过作用于Dlg介导的。我们还将探索内收蛋白/Hts如何发挥作用的其他方法，即使它的作用不是由Dlg介导的。例如，内收蛋白/Hts可能粘附在细胞膜上，充当支架，允许肌动蛋白和谱蛋白丝的细胞“骨架”结合，这对突触的结构很重要。

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.