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 proteinprotein 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. KeywordsIon channels; Cholesterol; Lipid rafts IntroductionDuring the last decade, a growing number of studies have demonstrated that the level of membrane cholesterol is a major regulator of ion channel function (reviewed by Maguy et al., 2006;Martens et al., 2004). It is also becoming increasingly clear that the impact of cholesterol on different types of ion channels is highly heterogeneous. The most common effect is cholesterol-induced decrease in channel activity that may include decrease in the open probability, unitary conductance and/or the number of active channels on the membrane. This effect was observed in several types of K + channels, voltage-gated Na + and Ca +2 channels, as well as in volume-regulated anion channels. However, there are also several types of ion channels, such as epithelial Na + channels (eNaC) and transient receptor potential (Trp) channels that are inhibited by the removal of membrane cholesterol. Finally, in some cases changes in membrane cholesterol affect biophysical properties of the channel such as the voltage dependence of channel activation or inactivation. Clearly, therefore, more than one mechanism has to be involved in cholesterol-induced regulation of different ion channels.

7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome

“…On the other hand, CHOL is a prominent component of the annular lipid belt around the transmembrane segment of ion channels thereby stabilizing the conformation of the channel [33]. It seems that VSDs and not the pore domain of Kv channels require the lipid belt [50].…”

“…Generally, the excess CHOL content of the plasma membrane suppresses the ion channel activity by reducing the open probability or conductivity. These suppressing effects were shown not only for Kv channels but for Ca 2+ and Na + channels as well [33]. On the other hand, some of the channels (e.g., TRPV channels and ENaC [33]) have been referred to as CHOL-dependent, whereby CHOL depletion reduces the activity of the channels.…”

“…These suppressing effects were shown not only for Kv channels but for Ca 2+ and Na + channels as well [33]. On the other hand, some of the channels (e.g., TRPV channels and ENaC [33]) have been referred to as CHOL-dependent, whereby CHOL depletion reduces the activity of the channels. We showed earlier that the CHOL loading of T cell membrane significantly slowed the activation and inactivation kinetics of Kv1.3 and modified the parameters of the steady-state activation [27].…”

Identification of a Binding Motif in the S5 Helix That Confers Cholesterol Sensitivity to the TRPV1 Ion Channel

“…Currents-Cholesterol is known to modify the trafficking of TRPV1 to the plasma membrane (17), as well as regulate the activity of some classes of channels (13). To isolate the effects of cholesterol on TRPV1 in the membrane from cellular trafficking processes, we measured currents from excised membrane patches of HEK293 cells containing heterologously expressed rat or human TRPV1.…”

“…Cholesterol can modify channel activity indirectly by altering the thickness and elastic properties of the surrounding lipid bilayer (14). In addition, in recent years compelling evidence has shown a specific interaction between cholesterol and several protein channels (13,15). That is, based on experiments with structural analogs of cholesterol and channels with specific point mutations, it has been found that cholesterol binds to certain channel proteins, including some with structural similarities to TRPV1 (16).…”