Dysfunction of GABA and glycine transporters in human neurological disease

中枢神经系统是一个复杂的，错综复杂的神经细胞（神经元）网络，其主要功能是传递和接收信息。这种交流发生在被称为突触的特殊接触部位。在这些部位，到达的神经冲动引起突触前细胞释放一种化学物质（神经递质），然后与嵌入相邻突触后神经元细胞膜中的受体分子相互作用。某些类型的受体（如甘氨酸和GABA-A受体）具有特异性离子渗透通道。这些通道响应神经递质的开放改变了细胞的电状态，或者传递或微妙地改变传入的神经冲动。然后，神经递质通过位于相邻神经胶质细胞或相应突触前细胞中的转运蛋白从突触中回收。调节突触传递和神经冲动活动的机制对于理解大脑的正常和疾病状态是重要的。事实上，许多正在使用或开发中的药物主要通过GABA或甘氨酸受体及其转运蛋白发挥作用。这些药物的治疗性质为进一步了解这些蛋白质的结构和功能的分子细节提供了令人信服的理由。这一建议将有利于在这一领域的研究，提高我们对GABA和甘氨酸转运蛋白的知识。在最近的一项研究中，我们能够证明甘氨酸转运蛋白GlyT 2的遗传缺陷是导致一种罕见疾病的原因，这种疾病称为hyperekplexia。这会影响新生儿，其特征是噪音或触摸引起的癫痫发作，导致屏气发作。在某些情况下，过度兴奋会导致脑损伤或婴儿猝死。我们的主要目标是：i）研究GlyT 2突变的后果，以揭示这些缺陷如何使转运蛋白失活，并研究在突触囊泡（VIAAT）上发现的甘氨酸转运蛋白或与GlyT 2相关的蛋白质中的缺陷是否也可引起高钾离子丛; ii）确定第二种甘氨酸转运蛋白GlyT 1中的基因突变是否导致不同的儿童疾病甘氨酸脑病的病例，这可能导致严重的脑损伤或死亡; iii）由于在某些类型的癫痫中发现了GABA受体的缺陷，我们将研究GABA转运蛋白基因的突变是否也会导致癫痫。我们希望详细了解导致这些疾病的遗传缺陷将有助于更好地诊断和治疗受影响的个人。

The central nervous system is a complex, intricate network of nerve cells (neurones) whose primary function is to transmit and receive messages. This communication occurs at specialised sites of contact known as synapses. At these sites, an arriving nerve impulse causes the release of a chemical (neurotransmitter) from the presynaptic cell which then interacts with receptor molecules embedded in the cell membrane of a neighbouring postsynaptic neurone. Some types of these receptors (e.g. glycine and GABA-A receptors) possess specific ion-permeable channels. The opening of these channels in response to neurotransmitter alters the electrical state of the cell either transmitting or subtly altering the incoming nerve impulse. Neurotransmitters are then recovered from the synapse by transporters located in neighbouring glial cells or the corresponding presynaptic cell. The mechanisms that regulate synaptic transmission and nerve impulse activity are important in understanding normal and diseased states of the brain. Indeed, many drugs in use or under development act primarily via GABA or glycine receptors and their transporters. The therapeutic nature of these agents provides a compelling reason for further understanding the molecular details of the structure and function of these proteins. This proposal will benefit research in this area by enhancing our knowledge concerning transporters for GABA and glycine. In a recent study we were able to show that genetic defects in the glycine transporter GlyT2 were responsible for causing a rare illness called hyperekplexia. This affects newborn children and is characterised by noise or touch-induced seizures which result in breath-holding episodes. In some instances hyperekplexia can lead to brain damage or sudden infant death. Our major aims are: i) to study the consequences of GlyT2 mutations to reveal how these defects disable the transporter, and to investigate whether defects in a glycine transporter found on synaptic vesicles (VIAAT) or proteins that associate with GlyT2 can also cause hyperekplexia; ii) to determine whether genetic mutations in a second glycine transporter, GlyT1, is responsible for cases of a different childhood illness, glycine encephalopathy, which can lead to severe brain damage or death; iii) since defects in GABA receptors are found in some types of epilepsy, we will investigate whether mutations in GABA transporter genes also cause epilepsy. It is our hope that a detailed understanding of the genetic defects responsible for these illnesses will enable better diagnosis and treatment of affected individuals.