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

Abstract

G protein-coupled receptors (GPCRs) are the largest class of molecules involved in signal transduction across cell membranes and represent major targets in the development of novel drug candidates in all clinical areas. Although there have been some recent leads, structural information on GPCRs is relatively rare due to the difficulty associated with crystallization. A specific reason for this is the intrinsic flexibility displayed by GPCRs, which is necessary for their functional diversity. Since GPCRs are integral membrane proteins, interaction of membrane lipids with them constitutes an important area of research in GPCR biology. In particular, membrane cholesterol has been reported to have a modulatory role in the function of a number of GPCRs. The role of membrane cholesterol in GPCR function is discussed with specific example of the serotonin 1A receptor. Recent results show that GPCRs are characterized with structural motifs that preferentially associate with cholesterol. An emerging and important concept is oligomerization of GPCRs and its role in GPCR function and signaling. The role of membrane cholesterol in GPCR oligomerization is highlighted. Future research in GPCR biology would offer novel insight in basic biology and provide new avenues for drug discovery.

Cholesterol: An evergreen molecule in biology

“…GPCRs are the largest class of molecules involved in signal transduction across membranes, and represent major targets in the development of novel drug candidates in all clinical areas [8,39,49]. Since GPCRs are integral membrane proteins, interaction of membrane lipids with them constitutes an important area of research in GPCR biology.…”

Interaction of lipids with the neurotensin receptor 1

“…[1][2][3][4]), with most reports focusing on the role of cholesterol and lipid microdomains influencing receptor activity, localisation, and G protein coupling in celulla. However, the molecular mechanisms that govern these interactions are poorly understood, and there is little information on how specific lipid species interact with GPCRs in membranes.…”

Cholesterol modulates bitter taste receptor function

“…An increasingly emerging feature in recently solved high resolution crystal structures of GPCRs is the presence of closely associated cholesterol molecules ( [31][32][33][34]; recently reviewed in [15]). Several structural motifs of proteins and receptors have been postulated to induce preferential association with cholesterol [13,15].…”

“…The role of membrane lipids in GPCR function is a promising and emerging area of research [11][12][13][14][15][16][17]. In this context, membrane cholesterol enjoys a unique position in modulating GPCR organization, dynamics and function [11][12][13][14][15][16]18].…”

“…In this context, membrane cholesterol enjoys a unique position in modulating GPCR organization, dynamics and function [11][12][13][14][15][16]18]. …”