Sensitivity of cholecystokinin receptors to membrane cholesterol content

Abstract

Cholesterol represents a structurally and functionally important component of the eukaryotic cell membrane, where it increases lipid order, affects permeability, and influences the lateral mobility and conformation of membrane proteins. Several G protein-coupled receptors have been shown to be affected by the cholesterol content of the membrane, with functional impact on their ligand binding and signal transduction characteristics. The effects of cholesterol can be mediated directly by specific molecular interactions with the receptor and/or indirectly by altering the physical properties of the membrane. This review focuses on the importance and differential effects of membrane cholesterol on the activity of cholecystokinin (CCK) receptors. The type 1 CCK receptor is quite sensitive to its cholesterol environment, while the type 2 CCK receptor is not. The possible structural basis for this differential impact is explored and the implications of pathological states, such as metabolic syndrome, in which membrane cholesterol may be increased and CCK1R function may be abnormal are discussed. This is believed to have substantial potential importance for the development of drugs targeting the CCK receptor.

A Type 1 Cholecystokinin Receptor Mutant That Mimics the Dysfunction Observed for Wild Type Receptor in a High Cholesterol Environment

“…This receptor has been shown to be uniquely sensitive to the membrane cholesterol composition (12,13), with the closely structurally related type 2 CCK receptor (CCK2R) not sensitive to membrane cholesterol (14). This effect has been demonstrated not only in model cell systems (15) but also in the natural cellular environment in animal models, such as the prairie dog fed a high cholesterol diet (16), and even in patients with cholesterol gallstones (17)(18)(19).…”

Beneficial effects of β-sitosterol on type 1 cholecystokinin receptor dysfunction induced by elevated membrane cholesterol

“…Of note, the closely-related CCK2R is not affected (4). This defect in CCK1R function is not observed in patients with pigment gallstones (3, 25), who are known to have similar levels of gallbladder inflammation, yet normal levels of cholesterol in their bile (27). Our previous in vitro studies using site-directed mutagenesis of CCK1R and model cell systems have suggested that the negative impact of elevated cholesterol on CCK1R function was mediated by a direct interaction between the two molecules resulting in an abnormal receptor conformation (5, 21).…”

“…This receptor is reported to exhibit dysfunction in the setting of high membrane cholesterol, such as has been reported in metabolic syndrome and cholesterol gallstone disease. Several in vitro and in vivo studies have demonstrated that the CCK1R is uniquely sensitive to an increase in cellular membrane cholesterol, which negatively affects effective coupling between Gq and this receptor, thereby resulting in reduced biological responses to CCK (see review (3)). Included among the defective biological responses is post-cibal satiety, contributing to increased weight gain and increasingly severe obesity.…”

Metabolic Actions of the Type 1 Cholecystokinin Receptor: Its Potential as a Therapeutic Target

“…Lateral allosterism through lipid interactions is now appreciated as a way to modulate GPCR function [49]. The CCK1R has been shown to be particularly sensitive to the cholesterol composition of the lipid bilayer [50, 51]. Membrane cholesterol elevated to levels reported in metabolic syndrome [52, 53], result in functional uncoupling of CCK binding from CCK-stimulated biological activity [50, 54–56].…”