Exocytosis, the fusion of vesicles with a membrane, is essential for cell-cell signaling between neurons. To better understand the mechanism behind alcohol’s impact on neuronal communication, we use a protein-free model of exocytosis to measure vesicle fusion with a planar membrane. Our previous studies have shown that when short-chain alcohols, especially ethanol, are delivered to the same side of the membrane as the vesicles ( cis , representing intracellular), a strong excitatory effect is seen. When alcohols are administered to the opposite side of the membrane ( trans , representing extracellular), an inhibitory effect is observed. From these data, we predicted that a symmetric addition of alcohols would be excitatory, similar to cis addition. Unexpectedly, symmetric addition decreased fusion rates, demonstrating that the excitation observed with cis addition is blocked by trans addition. This result was most pronounced with ethanol and propanol and less so with butanol. We reasoned that if ethanol and propanol predominantly remain asymmetric in the membrane leaflets, this would explain our cis results, whereas butanol partitions significantly and equilibrates quickly between both leaflets, consistent with decreased excitation from cis addition. To decrease butanol’s equilibration, we tested both 1,2 and 1,4-butanediols. We found that these diols inhibited fusion with cis , trans , or symmetric addition, demonstrating that these alcohols do not mimic the effects of ethanol and propanol. Additional ongoing projects include investigating the effects of volatile general anesthetics on vesicle fusion and building a biophysical model that predicts how alcohol partitioning into the membrane correlates with fusion rate.
Whitehead et al. (Sun,) studied this question.