Cholesterol and ion channels

Abstract

A variety of ion channels, including members of all major ion channel families, have been shown to be regulated by changes in the level of membrane cholesterol and partition into cholesterol-rich membrane domains. In general, several types of cholesterol effects have been described. The most common effect is suppression of channel activity by an increase in membrane cholesterol, an effect that was described for several types of inwardly-rectifying K(+) channels, voltage-gated K(+) channels, Ca(+2) sensitive K(+) channels, voltage-gated Na(+) channels, N-type voltage-gated Ca(+2) channels and volume-regulated anion channels. In contrast, several types of ion channels, such as epithelial amiloride-sensitive Na(+) channels and Transient Receptor Potential channels, as well as some of the types of inwardly-rectifying and voltage-gated K(+) channels were shown to be inhibited by cholesterol depletion. Cholesterol was also shown to alter the kinetic properties and current-voltage dependence of several voltage-gated channels. Finally, maintaining membrane cholesterol level is required for coupling ion channels to signalling cascades. In terms of the mechanisms, three general mechanisms have been proposed: (i) specific interactions between cholesterol and the channel protein, (ii) changes in the physical properties of the membrane bilayer and (iii) maintaining the scaffolds for protein-protein interactions. The goal of this review is to describe systematically the role of cholesterol in regulation of the major types of ion channels and to discuss these effects in the context of the models proposed.

Fig. 19.1

Regulation of an ion channel by annular lipids (from Barrantes (2004)). The diagram schematically shows a channel protein surrounded by specific lipid molecules that constitute the annular “belt” around the channel. The three panels illustrate the exchange process between the annular lipids and the bulk lipids of the membrane. A cholesterol molecule is proposed to be part of the lipid belt surrounding the channel. © Barrantes (2004). Originally published in Brain Research Reviews 47:71–95

Fig. 19.2

Hydrophobic coupling between channel conformational changes and lipid bilayer deformations. The diagram schematically shows a transition between the closed and the open states of an ion channel that is accompanied with a deformation of the lipid bilayer in the vicinity of the membrane. Membrane deformation involves compression and bending of the membrane leaflets, which is suggested to contribute the energetic cost of the channel opening. In this model, an increase in stiffness of the lipid bilayer is expected to increase the cost of the transition resulting in the inhibition of channel activity. © Lundbaek et al. (2004). Originally published in the Journal of General Physiology 123: 599–621 (Reproduced with permission)

Fig. 19.3

Chiral analogues of cholesterol have opposite effects on endothelial Kir currents. (A) Structure of cholesterol and epicholesterol. Cholesterol: R1=H, R2=OH; epicholesterol: R1=OH, R2=H. (B) Typical current traces recorded from a cell exposed to MβCD-epicholesterol and from a control cell. (C) Functional dependence of Kir current density on cholesterol and epicholesterol. Adapted from Romanenko et al. (2002)

Fig. 19.4

Identification of a cytoplasmic domain critical for the sensitivity of Kir2.1 channels to cholesterol. (A) Sequence of Kir WT with marked PIP₂-sensitive mutations analyzed for sensitivity to cholesterol and the homology model showing two opposite facing subunits of the channel with the positions of these residues. (B) Typical current traces of Kir2.1-WT, Kir2.1-R228Q, Kir2.1-K219Q and Kir2.1-N216D in control cells (grey) and in cells depleted of cholesterol (black) From Epshtein et al. (2009)

Fig. 19.5

Partitioning of different of Kv channels into distinct membrane domains. Lack of colocalization between Kv2.1 and Kv1.4 channels co-expressed in the same cells. (A) Kv2.1-CFP, (B) Kv1.4-YFP, (C) the overlay between Kv2.1 and Kv1.4 with Kv2.1-CFP pseudocolored green and Kv1.4-YFP pseudocolored red. (D) Fluorescence intensity profiles of Kv2.1-CFP and Kv1.4-YFP showing no or little correlation. From O′Connell and Tamkun (2005), published in the Journal of Cell Science 118: 2155–2166. Reproduced with permission)

Fig. 19.6

Differential regulation of GTPγS-activated VRAC by cholesterol depletion and substitution with its analogues. (A) The time-courses of VRAC current densities recorded in cells treated as indicated. (B) Normalized VRAC currents plotted as a function of the total sterol level in cells either depleted of or enriched with cholesterol (open circles) and in the cells, in which endogenous cholesterol was substituted with epicholesterol (diamonds), sitosterol (square), or coprostanol (triangle). In contrast to other two analogues, coprostanol could not substitute for cholesterol in regulation of VRAC, which is consistent with lack of strong effect of coprostanol on the physical properties of the membrane (Adapted from Romanenko et al., 2004b)