Regulation of glutamate transporter EAAT2 activity lateral diffusion and membrane trafficking by palmitoylation and interacting proteins

在我们的大脑中，信息被编码为神经细胞膜上电压的变化。神经细胞通过在被称为突触的特殊部位释放神经递质来相互传递信号。一种叫做谷氨酸的关键神经递质作用于特殊的蛋白质（受体），产生兴奋（更积极的电压）。控制可激活受体蛋白的神经递质谷氨酸的水平是调节大脑通讯的关键途径。控制大脑中谷氨酸的水平也很重要，因为如果谷氨酸水平过高，就会导致过度兴奋，这是有毒的，并可能导致神经元死亡（就像中风一样）。神经系统中的谷氨酸水平主要由脑细胞表面膜上的另一种蛋白质控制，这种蛋白质被称为转运蛋白。转运蛋白的特殊作用是将突触释放的谷氨酸结合在一起，并将其泵回细胞内，这样它就可以被包装和回收，从而阻止其累积到有毒水平。我的申请是在脑功能的一个关键方面：脑细胞如何调节脑细胞质膜中关键谷氨酸调节转运蛋白的数量、活动和位置，以控制突触神经递质信号的持续时间和强度。特别是，我们想研究谷氨酸转运蛋白的调节是如何进行的，表征蛋白质的分子特性，这对于调节转运蛋白的功能和在膜中的运动至关重要。研究这些调控过程背后的分子机制将使我们更好地了解大脑在健康条件下是如何工作的。此外，由于谷氨酸信号传导与许多神经退行性疾病和神经精神疾病有关，我们提出的工作也可能导致对神经递质谷氨酸水平改变的疾病的更好理解，如癫痫、中风、阿尔茨海默病、运动神经元疾病、亨廷顿氏病和精神分裂症。

In our brains information is encoded as changes in the voltage across the membrane of nerve cells. Nerve cells send signals to each other by releasing chemicals called neurotransmitters at special sites called synapses. One key neurotransmitter called glutamate acts on special proteins (receptors), to generate excitation (a more positive voltage). Controlling the levels of the neurotransmitter glutamate available to activate the receptor proteins is a key way to regulate communication in the brain. Controlling the levels of glutamate in the brain is also important because if glutamate levels get too high this causes too much excitation which is toxic and can lead to neuronal death (as occurs in stroke). Glutamate levels in the nervous system are mainly controlled by another type of protein on the surface membrane of brain cells, called a transporter protein. The transporters have a specialised role to bind glutamate released at synapses and pump it back inside cells so that it can be packaged up and recycled which stops it building up to toxic levels. My application is on a key aspect of brain function: how do brain cells regulate the number, activity and location of the key glutamate regulating transporter proteins in the plasma membrane of brain cells to control the duration and strength of neurotransmitter signaling at synapses. In particular we want to investigate how the regulation of the glutamate transporter proteins is performed, characterising the molecular properties of the proteins which are crucial for regulating transporter function and movement in the membrane. Studying the molecular mechanisms that underlie these regulatory processes will allow us to better understand how the brain works under healthy conditions. In addition because glutamate signalling is implicated in many neurodegenerative and neuropsychiatric diseases, our proposed work may also lead to an improved understanding of diseases where the levels of the neurotransmitter glutamate are altered such as epilepsy, stroke, Alzheimer's disease, motor neuron disease, Huntington's disease and schizophrenia.