Functional marriage in plasma membrane: Critical cholesterol level-optimal protein activity

Abstract

In physiology, homeostasis refers to the condition where a system exhibits an optimum functional level. In contrast, any variation from this optimum is considered as a dysfunctional or pathological state. In this review, we address the proposal that a critical cholesterol level in the plasma membrane is required for the proper functioning of transmembrane proteins. Thus, membrane cholesterol depletion or enrichment produces a loss or gain of direct cholesterol-protein interaction and/or changes in the physical properties of the plasma membrane, which affect the basal or optimum activity of transmembrane proteins. Whether or not this functional switching is a generalized mechanism exhibited for all transmembrane proteins, or if it works just for an exclusive group of them, is an open question and an attractive subject to explore at a basic, pharmacological and clinical level.

FIGURE 1

Two mechanisms of regulation of membrane proteins by cholesterol. Direct cholesterol–protein interactions and indirect regulation trough changes in the bilayer's physical properties. CARC, inverted CRAC sequence; Ch, cholesterol; CRAC, cholesterol recognition amino acid consensus; PL, phospholipids; TMP, transmembrane protein

FIGURE 2

Critical cholesterol concentration is necessary for the proper activity of plasma membrane proteins. Decrease and enrichment of cholesterol from the basal level result in alteration of membrane protein activity. Here are represented various possibilities of activity modification and representative examples of each one. In the centre of the illustration, the examples mainly discussed along this review are highlighted. Solid lines indicate experimental reported effects and the dashed lines the not yet described putative possibilities. A_2A, adenosine https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=19; CCK₁, cholecystokinin type 1 receptor; CCK₂, cholecystokinin type 2 receptor; GABA_A, GABA‐A receptor; K_ir, inwardly rectifying K⁺ channel; K_V, voltage‐dependent K⁺ channel; NCX, Na⁺/Ca²⁺ exchanger; Rhodo, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2963; https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=507 , transient receptor potential vanilloid 1