The role of alpha2delta subunits in calcium channel function under physiological and pathological conditions

我们正在试图了解一类用于治疗慢性疼痛的药物的作用机制。加巴喷丁及其新的相关药物普瑞巴林被用于缓解各种形式的慢性疼痛，包括带状疱疹后神经痛和糖尿病神经病变，尽管它们最初是为治疗某些类型的癫痫而开发的，对某些类型的癫痫也是有效的。最近的研究表明，这些药物是通过与一种蛋白质结合来发挥作用的，这种蛋白质构成了称为α2增量亚单位的钙通道的一部分。这些钙通道存在于所有的脑细胞中，对它们之间的交流是必不可少的。在几种慢性疼痛的动物模型中，损伤的神经细胞中α2Delta亚基的水平被发现增加。在这项研究中，我们现在希望从分子水平上了解这些α2Delta亚基是如何工作的，以及加巴喷丁与这些蛋白质的结合如何干扰它们的功能。为了做到这一点，我们将主要使用组织培养中的细胞，但在必要时，也将使用啮齿动物疾病模型。

We are trying to understand the mechanism of action of a class of drugs that are used in the treatment of chronic pain.The drugs, gabapentin, and its newer relative pregabalin, are used to alleviate various forms of chronic pain, including post-herpetic neuralgia and diabetic neuropathy, although they were originally developed for the treatment of certain types of epilepsy, for which they are also effective. Recent research has shown that these drugs have their effect by binding to a protein that makes up part of a calcium channel called the alpha2delta subunit. These calcium channels are present in all brain cells, and are essential for communication between them. In several animal models of chronic pain, the levels of alpha2delta subunits are found to increase in the damaged nerve cells.In this study we now hope to understand, at the molecular level, how these alpha2delta subunits work, and how the binding of gabapentin to these proteins interferes with their function. To do this we will mainly use cells in tissue culture, but also where necessary, rodent models of disease.