MOLECULAR BASIS OF ETHANOL ACTION ON CALCIUM CHANNELS

慢性心肌病的分子病因学研究进展 酒精消费没有确定。在其许多尖锐的行动中， 乙醇已经显示出抑制心脏L型Ca 2+通道。因为我- 型钙通道在兴奋-收缩偶联中起重要作用 在心脏中，已经提出，直接抑制这些 乙醇导致的慢性酒精性心肌病。 乙醇也可能通过以下途径间接影响钙通道活性： 调节β-肾上腺素能刺激或二氢吡啶 抑制这些通道。因此，拟议的研究将审查这两个问题， 乙醇作用的直接和间接机制。的长期目标 这一建议是：1）了解，在分子水平上，如何乙醇 抑制心脏L-型Ca 2+通道，和2）建立如何激素 刺激（肾上腺素）和抗癫痫药物（例如二氢吡啶类） 可以调节这种抑制。这个项目将应用互补DNA， 分子生物学、生物化学和细胞电生理学 （a）确定下列具体目标的方法： 有助于乙醇抑制的分子决定因素 重组L型Ca 2+通道; 2）表征生物物理特性 乙醇对重组L-型Ca 2+通道的影响;和3） 探讨内源性因素对抑制的调节作用 重组L-型钙通道。虽然这些目标是 关注心脏L型钙通道，也存在类似的通道 在其他可兴奋的组织中，如神经系统。在一些 提出的实验，大脑亚型的L型钙离子通道，以及 作为另外的神经元电压门控Ca 2+通道，将被研究。因此，在本发明中， 从酒精研究中心的这个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。

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.