MOLECULAR BASIS OF ETHANOL ACTION ON CALCIUM CHANNELS

乙醇对钙通道作用的分子基础

• 批准号: 6563159
• 负责人: MANEEL CAVARRUBIAS
• 金额: $ 13.07万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6563159
• 关键词: PC12 cells; Xenopus oocyte; alcoholism /alcohol abuse; antiarrhythmic agent; biophysics; calcium channel; calcium channel blockers; cardiotoxin; computer data analysis; disease /disorder etiology; drug interactions; electrophysiology; ethanol; hormone regulation /control mechanism; human fetus tissue; membrane lipids; microinjections; molecular biology; myocardium disorder; nucleic acid sequence; phosphorylation; polymerase chain reaction; protein kinase C; site directed mutagenesis; toxicant interaction; voltage /patch clamp; voltage gated channel

The molecular etiology of the cardiomyopathy associated with chronic alcohol consumption is not established. Among its many acute actions, ethanol has been shown to inhibit cardiac L-type ca2+ channels. Because L- type ca2+ channels play a crucial role in excitation-contraction coupling in the heart, it has been proposed that the direct inhibition of these channels by ethanol contributes to chronic alcoholic cardiomyopathy. Ethanol may also have indirect effects on ca2+ channel activity through the ability to modulate the beta-adrenergic stimulation or dihydropyridine inhibition of these channels. Thus, the proposed studies will examine both direct and indirect mechanisms for ethanol action. The long-term goals of this proposal are; 1) to understand, at the molecular level, how ethanol inhibits cardiac L-type Ca2+ channels, and 2) to establish how hormonal stimulation (epinephrine) and antiarrhythmic drugs (e.g. dyhydropyridines) may modulate such inhibition. This project will apply complementary DNA, molecular biological, biochemical and cellular electrophysiological methodologies to examine the following specific aims: 1) to characterize the molecular determinants that contribute to the ethanol inhibition of recombinant L-type Ca2+ channels; 2) to characterize the biophysical effects of ethanol on recombinant L-type Ca2+ channels; and 3) to investigate the modulatory effects of intrinsic factors on the inhibition of recombinant L-type Ca2+ channels by ethanoL. Although these aims are focused on cardiac L-type ca2+ channels, similar channels are also present in other excitable tissues, such as the nervous system. In some of the proposed experiments, brain isoforms of the L-type ca2+ channel, as well as additional neuronal voltage-gated ca2+ channels, will be studied. Thus, the results obtained from this component of the Alcohol Research Center should also be relevant to our understanding of ethanol action in both the heart and the nervous system.

与慢性有关的心肌病的分子病因 尚未确定饮酒。在许多急性行动中， 乙醇已显示可抑制心脏L型Ca2+通道。因为l- 类型Ca2+通道在激发触发耦合中起着至关重要的作用 在心中，有人提出直接抑制这些 乙醇的通道有助于慢性酒精性心肌病。 乙醇也可能对Ca2+通道活动有间接影响 调节β-肾上腺素能刺激或二氢吡啶的能力 抑制这些渠道。因此，拟议的研究将检查两者 乙醇作用的直接和间接机制。长期目标 该提议是； 1）在分子水平上了解乙醇 抑制心脏L型Ca2+通道，以及2）建立激素的方式 刺激（肾上腺素）和抗心律失常药物（例如染料吡啶） 可以调节这种抑制作用。该项目将应用互补的DNA， 分子生物学，生化和细胞电生理学 检查以下特定目的的方法：1）表征 有助于乙醇抑制的分子决定因素 重组L型Ca2+通道； 2）表征生物物理 乙醇对重组L型Ca2+通道的影响；和3）到 研究内在因素对抑制的调节作用 通过乙醇重组L型Ca2+通道的重组。尽管这些目标是 还针对心脏L型Ca2+通道，也存在类似的通道 在其他令人兴奋的组织中，例如神经系统。在某些 提出的实验，L型Ca2+通道的大脑同工型 由于将研究其他神经元电压门控Ca2+通道。因此， 从酒精研究中心的这一组成部分获得的结果 也应该与我们对乙醇作用的理解有关 心脏和神经系统。