structure32, raising the possibility that cholesterol may enhance the access of PIP2 to the channel. Thus, the site for cholesterol modulation is unlikely to be the same as that for alcohol (i.e. membrane vs. cytoplasmic). In addition, we noted functional differences between alcohol and cholesterol activation. First, there was no apparent shift in ethanol sensitivity in the presence of cholesterol. A direct or allosteric effect of alcohol on cholesterol activation might be reflected in differences in the dose-response curves. Second, the basal rate of K+ flux through GIRK2 channels in the presence of alcohol and a saturating level of cholesterol was higher than the rate for alcohol alone. Together, these results suggest that alcohol and cholesterol interact structurally and mechanistically with different regions of the channel.
