Ethanol is a wildly used drug of abuse with a complex and poorly understood mechanism of action. A major hurdle in understanding the mechanism of alcohol action is the large number of putative ethanol targets. While many cellular components are known to be effected by alcohol, the contributions of each target to the overall physiological and behavioral effects of alcohol are unknown. We propose a method for isolating the effects of ethanol at a single target without altering the wild-type system. We plan to utilize phage display technology to identify peptides that bind with high specificity at a single putative ethanol target, the glycine receptor (GlyR). These peptides will then be tested electrophysiologically for modulatory effects on the GlyR. The goal of the proposed work is to identify peptides that either mimic or antagonize the effects of ethanol on the GlyR without affecting other ethanol targets. The long term objective of this project is to isolate the contribution of individual putative ethanol targets by identifying highly selective small peptides that either mimic or antagonize the effects of ethanol at a single target. Peptides that mimic ethanol actions at a single target would allow researchers to simulate the application of ethanol to only that target. Conversely, co-application of a highly specific ethanol antagonist and ethanol would simulate the effects of ethanol on every target except the selected one. Essentially, the effects of ethanol on a single target could be isolated without disturbing the overall system. In this way, the role of the individual target plays in the expression of ethanol's effects could be identified. Understanding the importance of individual targets to ethanol consumption, addiction and behavioral effects will allow for the rational, targeted development of drugs to combat alcoholism.
|Tipps, Megan E; Iyer, Sangeetha V; John Mihic, S (2012) Trifluoroacetate is an allosteric modulator with selective actions at the glycine receptor. Neuropharmacology 63:368-73|
|Tipps, Megan E; Lawshe, Jessica E; Ellington, Andrew D et al. (2010) Identification of novel specific allosteric modulators of the glycine receptor using phage display. J Biol Chem 285:22840-5|