Lipid microdomains and the regulation of ion channel function

Abstract

Many types of ion channel localize to cholesterol and sphingolipid-enriched regions of the plasma membrane known as lipid microdomains or 'rafts'. The precise physiological role of these unique lipid microenvironments remains elusive due largely to difficulties associated with studying these potentially extremely small and dynamic domains. Nevertheless, increasing evidence suggests that membrane rafts regulate channel function in a number of different ways. Raft-enriched lipids such as cholesterol and sphingolipids exert effects on channel activity either through direct protein-lipid interactions or by influencing the physical properties of the bilayer. Rafts also appear to selectively recruit interacting signalling molecules to generate subcellular compartments that may be important for efficient and selective signal transduction. Direct interaction with raft-associated scaffold proteins such as caveolin can also influence channel function by altering gating kinetics or by affecting trafficking and surface expression. Selective association of ion channels with specific lipid microenvironments within the membrane is thus likely to be an important and fundamental regulatory aspect of channel physiology. This brief review highlights some of the existing evidence for raft modulation of channel function.

Figure 1. Lipid microdomains potentially influence ion channel activity by a variety of different mechanisms

Cartoon illustrating the segregation of different types of lipids in raft and non-raft regions of the plasma membrane. Cholesterol, sphingolipids and saturated phospholipids aggregate in tightly packed microdomains known as rafts. The lateral association of these lipids in the membrane is driven by tight hydrophilic and hydrophobic van der Waal interactions between sphingolipids and cholesterol (Simons & Ikonen, 1997). Cholesterol tends to increase the packing density in these regions by filling in the spaces between bulky sphingolipids. Sphingomyelin, the most prevalent sphingolipid, localizes predominantly to the outer leaflet of the membrane. In caveolar-type rafts, association with the cholesterol-binding protein caveolin causes the formation of flask-shaped invaginations of the surface membrane. Lipid microdomains may regulate channel function in a number of different ways. This regulation can occur by direct and indirect modulation by lipids; recruitment of interacting molecules to facilitate localized signalling; and/or modulation by caveolae-associated scaffold proteins, such as caveolin. This final form of modulation may be through direct alterations in channel kinetics or through changes in channel trafficking and surface expression. Additionally, the restricted opening at the mouth of the caveola would allow the build up of ions within the caveolar ‘pit’ to concentrations far in excess of that found in the bulk extracellular fluid. This would additionally influence the activity of proteins localized to these compartments.