Agonism and antagonism in cyclic nucleotide-gated channels

环核苷酸门控通道中的激动和拮抗作用

• 批准号: 312124-2011
• 负责人: Young, Edgar
• 金额: $ 2.19万
• 依托单位: Simon Fraser University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=571694
• 关键词: Agonism; antagonism; cyclic; nucleotide; gated

Cells control their life processes by producing natural chemical compounds (messengers) that bind to specific receptor proteins; in response, the receptors change their molecular structure in order to activate a particular biological function. Many physiological disorders, such as cancer and heart disease which afflict millions of Canadians, could be fought by artificial messengers (drugs) that either stimulate or suppress the ON- and OFF-switching of a specific receptor. My lab studies certain receptors called ion channels whose ON-conformation produces an electric current, so we can observe ON- and OFF-switching directly. We study a number of different ion channels, all of which respond to one type of messenger called cyclic nucleotide; this messenger is generated by the body under conditions of excitation, such as the "fight-or-flight" adrenaline rush, or during epileptic seizures in some parts of the brain. The molecules that form these ion channels all contain a specific sensing-domain which is the site for binding cyclic nucleotide. This sensing-domain obviously helps ON-switching after cyclic nucleotide is bound, but our lab has discovered that in different kinds of channels, the sensing-domain can do much more! For instance, in some channels, the sensing-domain will push the receptor OFF after being ON. These separate mechanisms reflect slight differences between the sensing-domains in different channels. We are finding what these key structural differences are: we change the ion channel's structure in a specific location ourselves by genetic engineering, and watch which of the different mechanisms are changed in consequence. In another strategy, certain chemical compounds bind the channel but their binding requires a very specific channel structure; we can thus use these compounds to test if that structure is present or absent in each of the separate mechanisms. We will thus learn how the basic blueprint for the sensing-domain can be modified in some details to produce very new actions. This will create a foundation of knowledge for engineering new actions in new versions of the sensing-domain.

细胞通过产生与特定受体蛋白结合的天然化合物（信使）来控制它们的生命过程；作为回应，受体改变其分子结构以激活特定的生物功能。许多生理疾病，如癌症和心脏病折磨着数百万加拿大人，可以通过人工信使（药物）来对抗，这种信使（药物）可以刺激或抑制特定受体的“开”和“关”开关。我的实验室研究一种叫做离子通道的受体，它的开构象产生电流，所以我们可以直接观察开和关的开关。我们研究了许多不同的离子通道，它们都对一种叫做环核苷酸的信使作出反应；这种信使是由身体在兴奋的情况下产生的，比如“战斗或逃跑”的肾上腺素激增，或者在大脑的某些部位癫痫发作时。形成这些离子通道的分子都含有一个特定的感应结构域，这是结合环核苷酸的位置。这种感应域显然有助于环核苷酸结合后的on开关，但我们的实验室发现，在不同的通道中，感应域可以做更多的事情！例如，在某些通道中，感觉域会在受体开启后将其关闭。