Investigating allosteric regulation by membrane domains of two pentameric ligand-gated ion channels.

Abstract

Ion channels are embedded in a compositionally heterogeneous membrane with nanoscale structure on the order of ∼10-100 nm. Experiments in giant plasma membrane vesicles suggest that one source of this heterogeneity is that the plasma membrane is poised near to but above a miscibility phase transition. Systems near a phase transition can have high susceptibility, meaning that physical properties are especially sensitive to external perturbations. Previous theoretical work in collaboration with Ben Machta has shown that small changes in the phase transition temperature, Tc, can have a strong influence on ion channel function when channels are coupled by boundary interactions to local changes in lipid composition. Meanwhile, data assembled from literature shows that n-alcohol treatments potentiate GABAA and glycine receptors by an amount that is well predicted by the treatment's corresponding shift in Tc. We hypothesize that these channels are allosterically regulated by local changes in lipid composition. From our model, we expect the channels to have strongly different lipid order preferences in their open versus closed states. In this poster, we present early investigations into this idea using two-color imaging of clustered receptors and membrane domain markers.