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.

Active cholesterol 20 years on

“…Other studies have suggested a role for cholesterol in the maturation, structure or function of integral plasma membrane proteins 177,178 . In particular, several G protein‐coupled receptors are regulated by the sterol 179,180 .…”

Cholesterol modulates the structural dynamics of the paddle motif loop of KvAP voltage sensor

“…It is also the most important functionally-relevant non-phospholipid in human health and disease. Due to its unique structural features, cholesterol affects the physical properties of model and biological membranes ( Yeagle, 1985 ; Meza et al, 2020 ). It is quite established that the distribution of cholesterol in the cellular membranes is not uniform, rather there exists a cholesterol gradient, i.e ., cholesterol is present at ∼35–45 mol% in the plasma membrane and is severely depleted in intracellular membranes ( Yeagle, 1985 ; van Meer et al, 2008 ; Subczynski et al, 2017 ).…”

“…Cholesterol is often laterally associated with sphingolipids in plasma membranes to form lateral membrane heterogeneities called functional microdomains or ‘rafts’ that have been implicated in various functions in mammalian cells ( Lingwood and Simons, 2010 ; Rao and Mayor, 2014 ; Kusumi et al, 2023 ). Importantly, cholesterol is a major regulator of the function of different classes of membrane proteins like ion channels, transporters and G-protein coupled receptors through direct and indirect effects ( Levitan et al, 2014 ; Zakany et al, 2020 ; Meza et al, 2020 ; Taghon et al, 2021 ; Yeagle, 2022 ). Particularly, cholesterol affects the functional activity of voltage-gated (K v ), inward rectifier K + (Kir), and BK channels ( Levitan et al, 2014 ; Zakany et al, 2020 ).…”

A basic model for cell cholesterol homeostasis

“…These acute shifts in free cholesterol not only serve as homeostatic feedback signals to cytoplasmic effectors but also modulate the activity of numerous PM proteins. 7,9,11,59 8. We chose a value of K1 PM = 5000 for the sterol association constant of PM phospholipids with a stoichiometry of C:P = 1:1.…”