MOLECULAR BASIS OF ETHANOL ACTION ON CALCIUM CHANNELS

乙醇对钙通道作用的分子基础

• 批准号: 6409967
• 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: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6409967
• 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.

慢性心肌病的分子病因学 饮酒量尚未确定。在其众多的尖锐行动中， 乙醇已被证明可以抑制心脏 L 型 ca2+ 通道。因为L- ca2+ 型通道在兴奋-收缩耦合中起着至关重要的作用 在心脏中，有人提出直接抑制这些 乙醇通道会导致慢性酒精性心肌病。 乙醇还可能通过以下方式对 ca2+ 通道活性产生间接影响： 调节β-肾上腺素能刺激或二氢吡啶的能力 抑制这些通道。因此，拟议的研究将检验两者 乙醇作用的直接和间接机制。的长期目标 该提案是； 1）在分子水平上了解乙醇如何 抑制心脏 L 型 Ca2+ 通道，2) 确定激素如何 兴奋剂（肾上腺素）和抗心律失常药物（例如二氢吡啶） 可以调节这种抑制。该项目将应用互补DNA， 分子生物学、生物化学和细胞电生理学 检查以下具体目标的方法：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) 生物物理特性 乙醇对重组L型Ca2+通道的影响； 3) 到 研究内在因素对抑制的调节作用 乙醇重组 L 型 Ca2+ 通道。尽管这些目标是 专注于心脏 L 型 ca2+ 通道，也存在类似的通道 在其他可兴奋的组织中，例如神经系统。在一些 提出的实验，L 型 ca2+ 通道的大脑亚型，以及 作为额外的神经元电压门控 ca2+ 通道，将被研究。因此， 从酒精研究中心的这个部分获得的结果 也应该与我们对乙醇作用的理解相关 心脏和神经系统。