Glycosylphosphatidylinositol (GPI)-anchoring of calcium channel alpha2delta subunits: function and pharmacology

糖基磷脂酰肌醇（GPI）-钙通道α2δ亚基的锚定：功能和药理学

• 批准号: G0901758/1
• 负责人: Annette Dolphin
• 金额: $ 122.94万
• 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: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0901758%2F1
• 关键词: Glycosylphosphatidylinositol; GPI; anchoring; calcium; channel

In patients, damage to peripheral nerves results from many different diseases, and can result in chronic pain that is poorly treated by most of the commonly used pain killers. Common conditions such as diabetes and recurrent herpes zoster infection (shingles), may result in such chronic pain. These conditions are termed post-herpetic neuralgia and diabetic neuropathy. Moreover, treatment with certain forms of cytotoxic chemotherapy can also cause nerve damage, which may be irreversible. These types of pain due to nerve damage are grouped under the umbrella term ?neuropathic pain?. At their mildest, the symptoms would be tingling in the extremities, and at their worst they can involve stabbing spontaneous pain, or pain resulting from light touch. A drug called gabapentin and its newer relative pregabalin (initially developed for the treatment of epilepsy) are effective for many patients in the alleviation of this type of neuropathic pain. Recent research has shown that gabapentin and pregabalin have their effect by binding to a protein (termed alpha2delta) that makes up part of a complex called a voltage-gated calcium channel. These calcium channels are present in all brain cells, and are essential for communication between them. Furthermore, the amount of this protein in pain-sensing nerves is increased several-fold in experimental models of neuropathic pain. Our study aims to examine some of the fundamental properties of these alpha2delta proteins, as we have recently discovered an exciting and novel aspect of their structure. We now hope to understand at the molecular level, how these alpha2delta proteins work, and how the binding of gabapentin (and related drugs) to these proteins interferes with their correct function. The more we know about the properties of these proteins, the better we will be able to understand how drugs such as gabapentin have their action, which is an essential first step in the development of novel and potentially more effective drugs in this class. This is important as not all patients obtain relief of neuropathic pain symptoms by taking gabapentin, and the reason for this is not well understood. We therefore hope that our research will aid in the development of novel drugs, that might have the potential to be more effective in certain patients or in certain conditions.

在患者中，周围神经的损伤由许多不同的疾病引起，并且可能导致慢性疼痛，大多数常用的止痛药治疗效果不佳。常见的疾病，如糖尿病和复发性带状疱疹感染（带状疱疹），可能会导致这种慢性疼痛。这些条件被称为带状疱疹后神经痛和糖尿病神经病变。此外，用某些形式的细胞毒性化疗治疗也会导致神经损伤，这可能是不可逆的。这些类型的疼痛，由于神经损伤是分组下的伞术语？神经性疼痛？最轻微的症状是四肢刺痛，最严重的症状是自发性刺痛或轻触引起的疼痛。一种叫做加巴喷丁的药物及其较新的相对普瑞巴林（最初是为治疗癫痫而开发的）对许多患者有效，可以缓解这种类型的神经性疼痛。 最近的研究表明，加巴喷丁和普瑞巴林通过与一种蛋白质（称为α 2 δ）结合而发挥作用，这种蛋白质构成了一种称为电压门控钙通道的复合物的一部分。这些钙通道存在于所有脑细胞中，并且对于它们之间的通信至关重要。此外，在神经性疼痛的实验模型中，这种蛋白质在痛觉神经中的量增加了几倍。 我们的研究旨在研究这些α 2 δ蛋白的一些基本特性，因为我们最近发现了它们结构的一个令人兴奋和新颖的方面。我们现在希望在分子水平上了解这些α 2 δ蛋白质是如何工作的，以及加巴喷丁（和相关药物）与这些蛋白质的结合如何干扰它们的正确功能。我们对这些蛋白质的性质了解得越多，我们就越能理解加巴喷丁等药物的作用机制，这是开发此类新型和潜在更有效药物的重要第一步。这一点很重要，因为并非所有患者都能通过服用加巴喷丁缓解神经性疼痛症状，其原因尚不清楚。因此，我们希望我们的研究将有助于开发新的药物，这些药物可能在某些患者或某些情况下更有效。