A Critical Analysis of Molecular Mechanisms Underlying Membrane Cholesterol Sensitivity of GPCRs

G protein-coupled receptors (GPCRs) are the largest and a diverse family of proteins involved in signal transduction across biological membranes. GPCRs mediate a wide range of physiological processes and have emerged as major targets for the development of novel drug candidates in all clinical areas. Since GPCRs are integral membrane proteins, regulation of their organization, dynamics, and function by membrane lipids, in particular membrane cholesterol, has emerged as an exciting area of research. Cholesterol sensitivity of GPCRs could be due to direct interaction of cholesterol with the receptor (specific effect). Alternately, GPCR function could be influenced by the effect of cholesterol on membrane physical properties (general effect). In this review, we critically analyze the specific and general mechanisms of the modulation of GPCR function by membrane cholesterol, taking examples from representative GPCRs. While evidence for both the proposed mechanisms exists, there appears to be no clear-cut distinction between these two mechanisms, and a combination of these mechanisms cannot be ruled out in many cases. We conclude that classifying the mechanism underlying cholesterol sensitivity of GPCR function merely into these two mutually exclusive classes could be somewhat arbitrary. A more holistic approach could be suitable for analyzing GPCR-cholesterol interaction.