Cholesterol and nicotinic acetylcholine receptor: An intimate nanometer-scale spatial relationship spanning the billion year time-scale

Abstract

Once the sterol biosynthetic machinery had progressed over the course of several million years to yield cholesterol, this neutral lipid became an omnipresent and essential component of biomembranes in Eukaryotes. The hopanoids in Prokary-otes and eukaryotic sterols share the ability to provide stability and domain compartmentalization in membranes. Even more important is the intimate association of cholesterol with a wide range of cell-surface membrane proteins, probably responsible for its modulatory effects on neurotransmitter and hormone receptors and ion channels. These effects appear to be exerted via the membrane-embedded segments of essentially all members of the pentameric ligand-gated ion channel and G-protein-coupled receptor superfamilies, which possess consensus linear arrays of amino acid residues recognizing cholesterol with relatively high affinity and specificity, an early evolutionary acquisition already present in ancient bacteria, conserved, and further improved in Eukaryotes. This review focuses on the long-term relationship between cholesterol and these functionally important membrane protein superfamilies, and the ability of cholesterol to induce lateral segregation and ordered domain formation at the nanoscale in cell membranes.