Towards an understanding of the molecular mechanisms that underlie the function of vascular ATP-sensitive potassium (KATP) channels

了解血管 ATP 敏感钾 (KATP) 通道功能的分子机制

• 批准号: BB/H000259/1
• 负责人: Paolo Tammaro
• 金额: $ 50.89万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH000259%2F1
• 关键词: Towards; understanding; molecular; mechanisms; underlie

High blood pressure is a risk factor for stroke and heart disease from which billions of people are suffering. Blood pressure is regulated by the diameter of the arteries through which the blood flows around the body. The diameter of these vessels is actively controlled by a surrounding layer of smooth muscle cells. Contraction of vascular smooth muscle narrows the arterial diameter and increases blood pressure. Conversely, its relaxation lowers blood pressure. On the inner wall of the artery is a layer of endothelial cells that regulate the function of smooth muscle. One of the important regulators of the contraction/relaxation process in vascular smooth muscle cells is a class of proteins known as ion channels, tiny gated pores that allow ions (such as potassium) to move into and out of the cell. The ATP-sensitive potassium (KATP) channels play a particularly important role in regulating the function of the cardiovascular system. A key feature of these channels is that their opening and closing is regulated by changes in the metabolic state of the cell. This is because they are modulated by the intracellular concentration of ATP, the molecule that serves as the energy currency of the cell. In the heart, KATP channels are especially active in times of cardiac stress, such as when blood flow is compromised (ischemia), and they help to protect against heart attack. In smooth muscle, however, they are important in regulating the resting level of vessel tone, and thus the diameter of the blood vessel. When these pores are open, vascular smooth muscle cells relax, lowering the blood pressure; when they are closed, contraction is favoured and blood pressure increases. Mice that lack KATP channels can die from a type of coronary vasospasm known as Prinzmetal syndrome that is also found in humans. It is therefore very important to understand how the opening and closing of the KATP channel is regulated. The aim of my studies is to determine the molecular mechanisms that underlie the function of vascular KATP channels, to elucidate how these are regulated by the energy metabolism of the cell, and to explore how mutations in KATP channel genes cause vascular disorders. I will use a number of experimental techniques to address these questions: from measurement of the passage of ions through a single ion channel to genetic modification of the KATP channel. I will also explore how drugs regulate vascular KATP channels. Such studies will provide us with a better understanding of how this channel operates under normal conditions and what goes wrong in disease states. They may also facilitate the development of novel drugs for the treatment of cardiovascular diseases such as hypertension and angina.

高血压是中风和心脏病的一个危险因素，数十亿人正在遭受这种疾病的折磨。血压是由动脉的直径调节的，血液通过动脉在身体周围流动。这些血管的直径由周围的平滑肌细胞层主动控制。血管平滑肌的收缩使动脉直径变窄，血压升高。相反，它的放松会降低血压。在动脉的内壁上是一层内皮细胞，其调节平滑肌的功能。血管平滑肌细胞收缩/舒张过程的重要调节因子之一是一类被称为离子通道的蛋白质，它们是允许离子（如钾）进出细胞的微小门控孔。ATP敏感性钾通道（KATP）在心血管系统的功能调节中起着特别重要的作用。这些通道的一个关键特征是它们的打开和关闭受细胞代谢状态变化的调节。这是因为它们受到细胞内ATP浓度的调节，ATP是细胞能量流通的分子。在心脏中，KATP通道在心脏应激时特别活跃，例如当血流受损（缺血）时，它们有助于防止心脏病发作。然而，在平滑肌中，它们在调节血管张力的静息水平以及因此调节血管的直径方面是重要的。当这些毛孔打开时，血管平滑肌细胞放松，降低血压;当它们关闭时，收缩有利，血压升高。缺乏KATP通道的小鼠可能死于一种冠状动脉血管痉挛，称为Prinzmetal综合征，这种综合征在人类中也有发现。因此，了解KATP通道的开放和关闭是如何调节的非常重要。我的研究目的是确定血管KATP通道功能的分子机制，阐明这些是如何通过细胞的能量代谢调节的，并探索KATP通道基因突变如何导致血管疾病。我将使用一些实验技术来解决这些问题：从测量离子通过单个离子通道到KATP通道的遗传修饰。我还将探讨药物如何调节血管KATP通道。这些研究将使我们更好地了解这一渠道在正常情况下如何运作，以及在疾病状态下出现了什么问题。它们还可能促进用于治疗心血管疾病如高血压和心绞痛的新药的开发。

项目成果

The TMEM16A anion channel as a versatile regulator of vascular tone

TMEM16A 阴离子通道作为血管张力的多功能调节器

• DOI: 10.1126/scisignal.adk5661
• 发表时间: 2023
• 期刊: Science Signaling
• 影响因子: 7.3
• 作者: Tammaro P

Disease-causing mutations associated with four bestrophinopathies exhibit disparate effects on the localization, but not the oligomerization, of Bestrophin-1.

• DOI: 10.1016/j.exer.2014.02.006
• 发表时间: 2014-04
• 期刊: EXPERIMENTAL EYE RESEARCH
• 影响因子: 3.4
• 作者: Johnson, Adiv A.;Lee, Yong-Suk;Chadburn, Andrew J.;Tammaro, Paolo;Manson, Forbes D.;Marmorstein, Lihua Y.;Marmorstein, Alan D.
• 通讯作者: Marmorstein, Alan D.