The function of G-protein coupled receptors and membrane cholesterol: specific or general interaction?

Abstract

Cholesterol is an essential component of eukaryotic membranes and plays a crucial role in membrane organization, dynamics and function. The G-protein coupled receptors (GPCRs) are the largest class of molecules involved in signal transduction across membranes and constitute ~1-2% of the human genome. GPCRs have emerged as major targets for the development of novel drug candidates in all clinical areas due to their involvement in the generation of multitude of cellular responses. Membrane cholesterol has been reported to have a modulatory role in the function of a number of GPCRs. This effect could either be due to specific molecular interaction between cholesterol and GPCR, or due to alterations in the membrane physical properties induced by cholesterol. Alternatively, membrane cholesterol could modulate receptor function by occupying the 'nonannular' sites around the receptor. In this review, we have highlighted the nature of cholesterol dependence of GPCR function taking a few known examples.

Seven Transmembrane Receptors as Shapeshifting Proteins: The Impact of Allosteric Modulation and Functional Selectivity on New Drug Discovery

“…Lipids are known to play important roles in 7TMR signaling (Escribá et al, 2007;Paila and Chattopadhyay, 2009). Many 7TMRs are themselves reversibly palmitoylated, typically within their carboxyl-terminal tail, where this modification helps to form a fourth intracellular loop region that has been shown to have regulatory properties.…”

Differential sensitivity of types 1 and 2 cholecystokinin receptors to membrane cholesterol

“…clear that cholesterol can be tightly associated with membrane proteins, including G protein-coupled receptors (GPCRs) (4)(5)(6), with this association capable of modifying the function and regulation of those proteins ( 7,(8)(9)(10). Of note, some sites of association of cholesterol with membrane proteins can be predicted by specifi c sequence motifs (11)(12)(13), although it is likely that these are not the only regions in which this lipid interacts with such membrane proteins.…”

GPCRs: Lipid-Dependent Membrane Receptors That Act as Drug Targets

“…As mentioned earlier, the role of cholesterol in the function and organization of membrane proteins and receptors constitutes an emerging and exciting area of research [36,[41][42][43][44]. Yet, the detailed mechanism underlying the effect of membrane cholesterol on the structure and function of membrane proteins and receptors is not clear and appears to be complex [43,59,60]. A possible mechanism by which membrane cholesterol has been proposed to modulate the function of membrane proteins is by a direct (specific) interaction, which could induce a conformational change in the receptor.…”