Biological and therapeutic roles of glycine receptors containing the alpha2 or alpha3 subunits

中枢神经系统（CNS）是一个复杂的神经细胞（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化学物质（神经递质）的释放，然后与嵌入相邻神经元细胞膜中的受体分子相互作用。这些受体的某些类型（例如甘氨酸受体）具有特定的离子渗透通道。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。调节突触传递和神经冲动活动的分子机制对于理解大脑的正常和疾病状态是重要的。事实上，许多主要药物主要通过受体/离子通道起作用。这些药物的治疗性质为进一步了解这类受体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，提高我们的知识，甘氨酸受体，抑制性离子通道，主要发现在脊髓和脑干。甘氨酸受体的动物模型和人体研究表明，一种受体亚型（称为α 1）与一种罕见的神经系统疾病（惊吓症）有关。通过创建一个敲除小鼠，其中另一个亚型（α 3）的基因被破坏，我们发现这在炎症性疼痛中很重要。炎症和慢性疼痛的新治疗靶标是当前的临床需求，因为经典镇痛剂的长期使用受到严重副作用的阻碍，例如胃溃疡导致老年人的显著死亡率，或者对于COX 2抑制剂，易患心脏病发作和中风。我们的主要目标是：i）确定α 2和α 3 GlyR在CNS中的分子变体和位置; ii）评估甘氨酸受体α 3亚基对炎症和慢性疼痛的贡献; iii）发现药物可能正调节含有α 1与α 3亚基的甘氨酸受体，这是开发新的疼痛治疗方法的第一步; iv）通过产生将缺乏这些受体的敲除小鼠来发现α 2亚型的作用。总之，我们的研究将为炎症和/或慢性疼痛的新治疗方法的开发提供信息，并可能揭示涉及α 2亚基基因缺陷的人类疾病。

The central nervous system (CNS) 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) which then interacts with receptor molecules embedded in the cell membrane of a neighbouring neurone. Some types of these receptors (e.g. glycine 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. The molecular mechanisms that regulate synaptic transmission and nerve impulse activity are important in understanding normal and diseased states of the brain. Indeed, many major drugs act primarily via receptor/ion channels. The therapeutic nature of these agents provides a compelling reason for further understanding the molecular details of the structure and function of this receptor class. This proposal will benefit research in this area by enhancing our knowledge concerning glycine receptors, inhibitory ion channels found mainly in the spinal cord and brainstem. Animal models and human studies of glycine receptors have shown that one receptor subtype (called alpha1) is involved in a rare neurological disorder (startle disease). By creating a knockout mouse where the gene for another subtype (alpha3) was disrupted, we found that this was important in inflammatory pain. New therapeutic targets for inflammatory and chronic pain are a current clinical need given that the long-term use of classical analgesics is hampered by severe side effects such as gastric ulcerations leading to significant mortality in the elderly or, for the COX2 inhibitors, a predisposition to heart attacks and stroke. Our major aims are: i) to characterise molecular variants and locations of the alpha2 and alpha3 GlyRs in the CNS; ii) to assess the contribution of the glycine receptor alpha3 subunit to inflammatory and chronic pain; iii) to discover drugs might positively modulate glycine receptors containing the alpha1 versus alpha3 subunits, the first step in developing new treatments for pain; iv) to discover the role of the alpha2 subtype by creating a knockout mouse which will lack these receptors. Taken together, our studies will inform the development of new therapeutic treatments for inflammatory and/or chronic pain and may uncover human disorders involving defects in the alpha2 subunit gene.