Wang X, Wang G, Lemos J R, Treistman S N
Department of Pharmacology, University of Massachusetts Medical School, Worcester 01655.
J Neurosci. 1994 Sep;14(9):5453-60. doi: 10.1523/JNEUROSCI.14-09-05453.1994.
Ingestion of ethanol results in a decreased level of plasma vasopressin, which appears to be caused by inhibition of arginine vasopressin (AVP) release from the neurohypophysis. Activation of membrane voltage-gated Ca2+ channels plays an important role in triggering this neurohormone release. In this article, single-channel recordings are used to demonstrate that ethanol, at concentrations constituting legal intoxication, inhibits dihydropyridine-sensitive "L-type" Ca2+ channels in isolated nerve terminals of the rat neurohypophysis. Ethanol reduced the channel open probability in a concentration-dependent manner. To allow finer resolution of channel openings and to better characterize the mechanisms of ethanol action, Bay K 8644 was used to prolong the openings of L-type Ca2+ channels. In the presence of this dihydropyridine (DHP), the reduction of the channel open probability by concentrations of ethanol of 25 mM or higher could be determined to be due primarily, although not completely, to a shortening of the open duration of this L-channel. Channel conductance was unaffected by ethanol, even at high concentrations. These results are consistent with previous macroscopic data indicating that calcium channels in these peptidergic terminals are targets for ethanol action, and indicate that ethanol acts directly on the gating characteristics of the L-type channel. Furthermore, examination of open and closed state transitions, as well as Hill plot analysis, suggests that ethanol's effects on gating are consistent with the interaction of a single drug molecule with a single target site, possibly the L-channel itself.
摄入乙醇会导致血浆血管加压素水平降低，这似乎是由于神经垂体中精氨酸血管加压素（AVP）释放受到抑制所致。膜电压门控Ca2+通道的激活在触发这种神经激素释放中起重要作用。在本文中，单通道记录用于证明，在构成法定中毒浓度的乙醇作用下，大鼠神经垂体分离神经末梢中的二氢吡啶敏感“L型”Ca2+通道受到抑制。乙醇以浓度依赖的方式降低通道开放概率。为了更精细地分辨通道开放情况并更好地表征乙醇作用机制，使用Bay K 8644来延长L型Ca2+通道的开放时间。在这种二氢吡啶（DHP）存在的情况下，可以确定25 mM或更高浓度的乙醇对通道开放概率的降低主要（尽管不是完全）是由于该L通道开放持续时间缩短所致。即使在高浓度下，通道电导也不受乙醇影响。这些结果与先前的宏观数据一致，表明这些肽能末梢中的钙通道是乙醇作用的靶点，并表明乙醇直接作用于L型通道的门控特性。此外，对开放和关闭状态转换的检查以及希尔图分析表明，乙醇对门控的影响与单个药物分子与单个靶点（可能是L通道本身）的相互作用一致。
