Mechanisms of glycine receptor modulation by ethanol

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DESCRIPTION (provided by applicant): Glycine Receptors (GlyRs) play a significant role in mediating the in vivo responses to ethanol exposure. Despite numerous studies characterizing the direct effects of ethanol on GlyRs, the molecular mechanisms of ethanol modulation of GlyR function remain unknown. We propose to use patch clamp electrophysiology to investigate the effects of ethanol on the single-channel properties of GlyR function. A mutant alphal GlyR (D97R) that spontaneously cycles between closed, open, and desensitized states in the absence of neurotransmitter will allow us to directly probe ethanol effects on GIyR activity while removing the neurotransmitter binding and unbinding variables that confound most studies of ligand-gated ion channel modulation. The proposed experiments will test the hypothesis that ethanol and related compounds, including a number of inhalants and volatile anesthetics, modulate GlyR function by stabilizing the receptor open conformation. An understanding of the molecular mechanisms of alcohol action will aid in the rational development of pharmaceuticals to treat alcoholism.