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

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.