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

含有 α2 或 α3 亚基的甘氨酸受体的生物学和治疗作用

• 批准号: G0500833/1
• 负责人: Robert Harvey
• 金额: $ 65.99万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0500833%2F1
• 关键词: Biological; therapeutic; roles; glycine; receptors

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.

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，到达的神经冲动会导致一种化学物质（神经递质）的释放，这种化学物质随后会与嵌入在邻近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。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病变状态非常重要。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。这一建议将有利于这一领域的研究，增强我们对主要存在于脊髓和脑干的甘氨酸受体、抑制离子通道的认识。动物模型和对甘氨酸受体的人体研究表明，一种受体亚型（称为alpha1）与一种罕见的神经系统疾病（惊吓病）有关。通过创建一个敲除小鼠，其中另一种亚型（alpha3）的基因被破坏，我们发现这在炎症性疼痛中很重要。针对炎症和慢性疼痛的新治疗靶点是当前的临床需要，因为经典镇痛药的长期使用受到严重副作用的阻碍，如胃溃疡导致老年人显著死亡率，或者COX2抑制剂易导致心脏病发作和中风。我们的主要目标是：i)表征中枢神经系统中alpha2和alpha3 GlyRs的分子变异和位置；Ii)评估甘氨酸受体α 3亚基在炎症和慢性疼痛中的作用；Iii)发现可能正向调节含有alpha1和alpha3亚基的甘氨酸受体的药物，这是开发新的疼痛治疗方法的第一步；Iv)通过创建缺乏这些受体的敲除小鼠来发现alpha2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。