Dysfunction of GABA and glycine transporters in human neurological disease

中枢神经系统是一个由神经细胞（神经元）组成的复杂网络，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）具有特定的离子渗透通道。这些通道的打开对神经递质的反应改变了细胞的电状态，传递或微妙地改变了传入的神经冲动。神经递质随后由位于邻近胶质细胞或相应的突触前细胞中的转运体从突触中恢复。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病变状态非常重要。事实上，许多正在使用或正在开发的药物主要通过GABA或甘氨酸受体及其转运体起作用。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。这一建议将通过提高我们对GABA和甘氨酸转运体的认识而有利于这一领域的研究。在最近的一项研究中，我们能够证明甘氨酸转运体GlyT2的遗传缺陷导致了一种罕见的疾病——过度增生。它影响新生儿，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，过度臂丛症会导致脑损伤或婴儿猝死。我们的主要目标是：i)研究GlyT2突变的后果，揭示这些缺陷是如何使转运蛋白失活的，并研究在突触囊泡（VIAAT）或与GlyT2相关的蛋白质上发现的甘氨酸转运蛋白缺陷是否也会导致过度增生；ii)确定第二种甘氨酸转运体GlyT1的基因突变是否与另一种儿童疾病甘氨酸脑病有关，这种疾病可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转运体基因的突变是否也会导致癫痫。我们希望对导致这些疾病的遗传缺陷的详细了解将有助于更好地诊断和治疗受影响的个体。

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.