Vascular KATP Channel Modulation in Hypercapnic Acidosis

高碳酸血症性酸中毒中的血管 KATP 通道调节

基本信息

批准号：
7080404
负责人：
CHUN JIANG
金额：
$ 28.42万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2008-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7080404
关键词：
Xenopus acid base balance adenosine diphosphate adenosine triphosphate carbon dioxide histidine hydrogen ions intermolecular interaction laboratory rat phosphatidylinositols potassium channel protein isoforms protein sequence protein structure function reactive hyperemia respiratory acidosis vascular smooth muscle

项目摘要

DESCRIPTION (provided by applicant): ATP-sensitive K+ channels (KATP) couple the intermediary metabolism to cellular excitability, and play an important role in reactive hyperemia. It is known that hyperemia underlies the cardio-protective effect of ischemic preconditioning and the activity-dependent auto-regulation of cerebral circulation, and involves sensing of O2, CO2 and pH. Our recent studies indicate that KATP channels are indeed activated with high COz / low pH. The regulation of KATP by protons is significant, because a drop in pH levels often accompanies various metabolic stresses and is more frequently seen than sole energy depletion. Such regulation may enable cells to change their membrane excitability in response to a wide variety of physiologic and pathophysiologic conditions. However, previous studies on the pH sensitivity were rather controversial: proton was shown to stimulate cell-endogenous KATP in some studies but inhibit it in others. The inconsistence is further complicated by the indirect effect of ATP, ADP and Mg ++ on channel activity. Thereby, it is unclear how the KATP is modulated during hypercapnia and acidosis, whether these channels are inherently pH-sensitive, and what the molecular mechanisms underlying the modulation are. The cloned KATP channels are ideal for addressing these questions, which allow a fine dissection of the modulatory mechanisms and elaborate manipulations of PCO2 and pH in the expression system. Thereby, we have been studying the pH sensitivity of the cloned KATP over the past 3 years. Our preliminary data have clearly shown that proton is a potent activator of the KATP. TO further these observations, we have proposed studies aimed at 1) elucidating the modulation of KATP by hypercapnia and acidosis, 2) demonstrating the sensing mechanisms in the channel proteins, 3) determining factors and their interactions with protons in regulating the pH sensitivity, and 4) identifying the pH-sensitive KATP isoforms in vascular smooth muscles. This information should have profound impacts not only on cardiovascular physiology but also on the design of therapeutical modalities by manipulating the pH-sensing mechanisms to control cellular activity in stroke, epilepsy and coronary heart disease.

描述（由申请人提供）：ATP敏感的K+通道（KATP）将中介代谢与细胞兴奋性息息相关，并在反应性充血中发挥重要作用。众所周知，充血是缺血性预处理的心脏保护作用以及脑循环的活性依赖性自动调节的基础，涉及O2，CO2和pH的感应。我们最近的研究表明，KATP通道确实被高COZ /低pH激活。质子对KATP的调节非常重要，因为pH值下降通常伴随着各种代谢应力，并且比唯一的能量耗尽更常见。这种调节可以使细胞能够响应各种生理和病理生理状况而改变其膜兴奋性。然而，先前关于pH敏感性的研究存在争议：在某些研究中，质子显示出质子刺激细胞源性KATP，但在其他研究中抑制了质子。 ATP，ADP和MG ++对通道活动的间接影响更加复杂，不一致。因此，目前尚不清楚如何在高碳酸盐和酸中毒期间调制KATP，这些通道是否固有地对pH敏感，以及调制调制的分子机制是什么。克隆的KATP通道是解决这些问题的理想选择，可以很好地解剖调节机制，并在表达系统中对PCO2和PH进行了精心的操纵。因此，在过去的三年中，我们一直在研究克隆KATP的pH敏感性。我们的初步数据清楚地表明，质子是KATP的有效激活剂。 TO further these observations, we have proposed studies aimed at 1) elucidating the modulation of KATP by hypercapnia and acidosis, 2) demonstrating the sensing mechanisms in the channel proteins, 3) determining factors and their interactions with protons in regulating the pH sensitivity, and 4) identifying the pH-sensitive KATP isoforms in vascular smooth muscles.这些信息不仅应该对心血管生理学产生深远的影响，而且还应通过操纵pH值机制来控制中风，癫痫和冠心病的细胞活性来对治疗方式的设计产生深远的影响。