Role of sterols in modulating the human mu-opioid receptor function in Saccharomyces cerevisiae

This study provides evidence that the differences in membrane composition f ound from one cell type to another can represent a limiting factor to recov ering the functionality of transmembrane proteins when expressed in heterol ogous systems. Restoring the properties of the human mu -opioid receptor in yeast (Saccharomyces cerevisiae), similar to those observed in native cell s, was achieved by replacing ergosterol from yeast by cholesterol, which is normally found in mammalian plasma membranes. The results suggest that the se two sterols have opposite effects with respect to the ligand binding fun ction of the receptor. Ergosterol was found to constrain the Cr-opioid rece ptor in an inactive state in yeast plasma membranes and cannot replace chol esterol in activating it. These data differ from previous works dealing wit h the function of related G-protein-coupled receptors (GPCR) in ergosterol- enriched membranes. This suggests that structural requirements of GPCR with respect to their modulation by lipid components differ from one protein to another. As a consequence, we assume that the presence of appropriate lipi ds around transmembrane proteins determines their function. This highlights the functional significance of lateral heterogeneities of membrane compone nts within biological membranes.