Ethanol Modulation of Zinc-Activated Channels

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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.