Journal of Proteomics & Bioinformatics
Open Access
ISSN: 0974-276X
ISSN: 0974-276X
Irena Levitan and Nicholas Barbera
University of Illinois at Chicago, USA
Posters & Accepted Abstracts: J Proteomics Bioinform
Numerous ion channels have been shown to be regulated by the level of membrane cholesterol but the mechanisms responsible for these effects are still not well understood. The key question in the field is how to discriminate between the contributions of the two central mechanisms that might be responsible for the sensitivity of ion channels to cholesterol: specific sterol-protein interactions or regulation of channels by the bilayer physical properties. Our studies focus on inwardly rectifying K+ (Kir) channels that are ubiquitously expressed in mammalian cells and are known to play major role in membrane excitability and shear stress sensation. We have shown that Kir channels are suppressed by loading the cells with cholesterol and enhanced by cholesterol depletion. Comparative analysis of cholesterol and its isomers on the function of Kir revealed that cholesterol regulates these channels in a stereo-specific manner, suggesting an involvement of specific sterol�??protein interactions. Furthermore, we present new evidence that the stereo specificity of cholesterol�??ion channel interactions may be mediated, not by a lack of binding, has been generally assumed, but by the specificity of the interaction, which results in a functional effect, in the case of native cholesterol and a lack of functional effect in the case of a cholesterol isomer. In other words, accumulating evidence suggests that the structural requirements of ion channel cholesterol-binding sites are lax, allowing chiral isomers of cholesterol to bind to the same site in a non-stereospecific way, but the ability of a sterol to confer a functional effect on the channel activity can still be stereospecific. This is an important distinction both conceptually and methodologically. Indeed, our analysis shows that the orientations of cholesterol and its chiral isomer ent-cholesterol within a hydrophobic binding pocket of Kir 2.2 are significantly different and we propose that this difference may underlie distinct functional outcomes.