ETHANOL AND RELEASABLE STORES OF INTRACELLULAR CALCIUM

以前的研究表明，乙醇和其他麻醉剂增加， 神经元和非神经元细胞内静息钙浓度 组织中这种效应可能是乙醇/麻醉剂诱导的 增加依赖于细胞内钙的机制，包括 静息神经递质释放和钙依赖性钾 电导率在这个提议中。假设乙醇增加了 静息细胞内钙浓度通过释放钙从 非线粒体细胞内储存位点。这种钙储存也可能 可由其他麻醉剂释放，但可与 第二信使三磷酸肌醇释放的钙库 在许多不同的组织中产生， 刺激.在拟议的研究中， 乙醇和其他麻醉剂释放的细胞内钙储存， 由三磷酸肌醇释放的钙储存将被定义在 脑和肝组织以及PC 12细胞中。的潜在机制 乙醇/麻醉剂诱导的细胞内钙释放 也要区别对待。乙醇诱导的钙释放的作用 这种细胞内钙储存在耐受性和依赖性的发展中 将被评估。这种乙醇敏感性的可能的内源性调节剂 还将研究钙储存。的存在 乙醇/麻醉剂可释放的钙储存在大脑和肝脏中表明 拟议研究的结果可能会影响到 乙醇滥用和成瘾以及急性毒性的药物治疗 酒精和其他麻醉剂的影响。

Previous work showed that ethanol and other intoxicant-anesthetics increase resting intracellular calcium concentrations in neuronal and non-neuronal tissues. This effect may be responsible for ethanol/anesthetic-induced increases in mechanisms dependent on intracellular calcium including resting neurotransmitter release and calcium-dependent potassium conductances. In this proposal. it is hypothesized that ethanol increases resting intracellular calcium concentrations by releasing calcium from a non-mitochondrial intracellular storage site. This calcium store may also be released by other anesthetic agents but is distinguishable from the calcium store released by inositol trisphosphate a second messenger generated in many different tissues following receptor-mediated stimulation. In the proposed studies, the relationship between the intracellular calcium stores released by ethanol and other anesthetics and the calcium stores released by inositol trisphosphate will be defined in tissues from brain and liver and in PC12 cells. Potential mechanisms of ethanol/anesthetic-induced calcium release from intracellular stores will also be distinguished. The role of ethanol-induced calcium release from this intracellular calcium store in tolerance and dependence development will be evaluated. Possible endogenous regulators of this ethanol-sensitive calcium store will also be investigated. The presence of an ethanol/anesthetic-releasable calcium store in brain and liver indicates that findings from the proposed studies may have bearing on possible pharmacological treatments for ethanol abuse and addiction and acute toxic effects of ethanol and other anesthetics.