MOLECULAR BASIS OF ETHANOL ACTION ON CALCIUM CHANNELS

乙醇对钙通道作用的分子基础

• 批准号: 6267084
• 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: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6267084
• 关键词: PC12 cells; Xenopus oocyte; alcoholism /alcohol abuse; antiarrhythmic agent; biophysics; calcium channel; calcium channel blockers; cardiotoxin; 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.

与慢性心肌病相关的分子病因