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Heusser SA1, Voigt TB2, Khan NN3, Horani S3, Harris RA3, Lindahl E1, Howard RJ2

1Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, Stockholm, Sweden
2Department of Chemistry, Skidmore College, Saratoga Springs, NY, USA
3Waggoner Center for Alcohol & Addiction Research, The University of Texas at Austin, Austin, TX, USA

Although they influence a wide range of targets, alcohols have distinct effects on different brain receptors. For example, ligand-gated ion channels involved in pain, motor coordination, consciousness, and reward can be positively or negatively modulated by alcohols, and with varying chain-length cutoffs. A growing catalog of atomic-resolution structures has enabled increasingly detailed studies of alcohol binding to ion channels. In the case of the capsaicin receptor (TRPV1), we found that n-alcohols potentiated responses to structurally distinct agonists, with a cutoff around five carbons. These effects were observed even in a simplified heterologous expression system, and were not ablated by disrupting phosphorylation or lipid-mediated signaling. In the case of pentameric ligand-gated ion channels (Cys-loop receptors), ethanol potentiation was quantitatively transferred between human and bacterial subtypes via the transmembrane domain, specifically an intersubunit binding site evidenced by co-crystallization. Functional characterization of receptor mutants provided a model for sensitivity to small changes in size and shape in the alcohol binding site, and for differential stabilization of functional receptor states by alcohol. Comparison to recent eukaryotic structures supported a conserved site of alcohol modulation in this channel family, but also revealed inconsistencies with common mechanistic models. Ongoing refinement of physicochemical determinants and/or functional model states promises to validate a conserved mechanism for alcohol modulation in these systems.