Ethanol Modulation of Zinc-Activated Channels

描述(由申请人提供)：人类急性酒精暴露会导致记忆损害，类似于海马体损害造成的损害。成像研究显示，与非酗酒者相比，酗酒者的海马体较小；然而，酒精对海马体造成损害的潜在机制尚不清楚。锌激活通道(ZAc)是乙醇敏感的Cys环配体门控阳离子通道超家族的新成员，受过渡金属、锌和铜的门控。Zac基因在啮齿类动物中是一个无功能的伪基因。然而，在人类中，该基因在胎儿大脑和成年大脑中由富含锌和铜的海马神经元神经支配的区域编码Zac mRNA。我的初步数据显示，酒精在令人陶醉的浓度下，会增强表达Zac通道的细胞的铜诱发电流。根据ZAC与5-HT3A和烟酸α7亚基的结构相似性，预测ZAC具有钙通透性。从生理上讲，乙醇增强Zac介导的信号将增加突触后钙信号。过度刺激会使神经元暴露在兴奋性毒性的风险中。基于这些数据，我形成了我的中心假设：ZAC是一种钙离子通道，乙醇稳定了开放的通道状态，导致激动剂敏感性增加，失活和脱敏动力学变慢。为了验证这一假设，我将追求三个具体目标：1)建立ZAC通道对乙醇的敏感性。2)研究乙醇对ZAC通道动力学的影响。3)测定ZAC通道的钙通透性。这项研究具有非常重要的意义，因为它将阐明酒精对已知由锌和铜神经元支配的海马神经元的损伤机制。 与公共健康相关：在人类中，酗酒会导致记忆障碍，这被认为是由于大脑中一种名为海马体的部位受损所致。酒精对海马体的损伤机制还知之甚少。这个项目着眼于在海马体中发现的一种新的酒精敏感蛋白，该蛋白是最容易受到酒精损害的区域，并检查了酒精对该蛋白的作用。

DESCRIPTION (provided by applicant): Acute alcohol exposure in humans results in memory impairments similar to the impairments caused by hippocampal damage. Imaging studies reveal a smaller hippocampus in those people who abuse alcohol as compared to non-abusers; however, the mechanisms underlying such alcohol-mediated damage to the hippocampus are poorly understood. The zinc activated channel (ZAC) is a novel member of the alcohol sensitive Cys-loop ligand-gated cation channel superfamily and is gated by the transition metals, zinc and copper. The gene encoding for ZAC is a non-functional pseudo-gene in rodents. However, in humans the gene encodes ZAC mRNA in fetal brain and in areas of the adult brain that are innervated by zinc and copper enriched hippocampal neurons. My preliminary data show that ethanol, at intoxicating concentrations, potentiates copper-evoked currents from cells expressing ZAC channels. Based on structural similarities with 5-HT3A and nicotinic alpha 7 subunits, ZAC is predicted to be calcium permeable. Physiologically, an enhancement by ethanol of a ZAC- mediated signal would increase post-synaptic calcium signaling. Excessive stimulation would expose the neuron to risk of excitotoxicity. Based on these data I have formed my central hypothesis: ZAC is a calcium permeable ion channel and ethanol stabilizes the open channel state, resulting in increased agonist sensitivity and slower deactivation and desensitization kinetics. To test this hypothesis I will pursue three specific aims: 1) Establish the sensitivity of ZAC channels to ethanol. 2) Characterize ZAC channel kinetics and their alteration by ethanol. 3) Determine the calcium permeability of ZAC channels. This research is highly significant as it will elucidate the mechanisms of alcohol-mediated damage to human hippocampal neurons in areas known to be innervated by zinc and copper neurons. PUBLIC HEALTH RELEVANCE: In humans, alcohol abuse results in memory impairments thought to be caused by damage to a part of the brain called the hippocampus. The mechanisms of alcohol mediated damage to the hippocampus are poorly understood. This project looks at a new alcohol sensitive protein found in the areas of the hippocampus that is most at risk from alcohol damage and examines the actions of alcohol on this protein.