Regulation of Ion Channels by Membrane Lipids

Abstract

The major membrane lipid regulators of ion channel function include cholesterol, one of the main lipid components of the plasma membranes, phosphoinositides, a group of regulatory phospholipids that constitute a minor component of the membrane lipids but are known to play key roles in regulation of multiple proteins and sphingolipids, particularly sphingosine-1-phosphate, a signaling biolipid that is generated from ceramide and is known to regulate multiple cellular functions. Furthermore, specific effects of all the lipid modulators are highly heterogeneous varying significantly between different types of ion channels, as well as between different cell types. In terms of the mechanisms, three general mechanisms have been shown to underlie lipid regulation of ion channels: specific lipid-protein interactions, changes in the physical properties of the membrane, and facilitating the association of the channel proteins with other regulatory proteins within multiproteins signaling complexes termed membrane rafts. In this article, we present comprehensive analysis of the roles of several lipid modulators, including cholesterol, bile acids, phosphoinositides, and sphingolipids on ion channel function.

Identification of Novel Cholesterol-binding Regions in Kir2 Channels

“…As hinted by its name, the CARC motif, (R/K)X [1][2][3][4][5] Our data show that there is a partial overlap between the first CARC motif and the cholesterol-binding region that we have identified at the interface of the TM domain with the cytosolic domain (putative cholesterol-binding region 2). Specifically, as we have shown in Fig.…”

“…An increase in membrane cholesterol has been shown to regulate different types of K ϩ channels, Ca 2ϩ channels, Na ϩ channels, and Cl Ϫ channels, as described in detail in several recent reviews (1)(2)(3)(4). The most common effect of cholesterol on ion channels is a decrease in channel activity that may be due to a decrease in the open probability, in the unitary conductance, and/or in the number of active channels in the membrane.…”

“…The members of this subfamily of constitutively active, strongly inwardly rectifying K ϩ (Kir) 4 channels are critically involved in regulation of the excitability and contraction in a variety of cell types and in maintaining the membrane potential in several types of non-excitable cells (9 -11).…”

Cholesterol sensitivity of KIR2.1 depends on functional inter-links between the N and C termini

“…[3][4][5] In recent years, it has been demonstrated to regulate the function of almost all known families of ion channels including K + channels, Ca 2+ channels, Na + channels and Cl − channels, as described in detail in several recent reviews. [6][7][8] For the majority of the channels, increased levels of membrane cholesterol resulted in decreased channel activity due to a decrease in the open probability, in the unitary conductance and/or in the number of active channels in the membrane. [8][9][10][11][12][13] Yet, the mechanisms of cholesterol regulation of ion channel function are only starting to emerge.…”

“…[6][7][8] For the majority of the channels, increased levels of membrane cholesterol resulted in decreased channel activity due to a decrease in the open probability, in the unitary conductance and/or in the number of active channels in the membrane. [8][9][10][11][12][13] Yet, the mechanisms of cholesterol regulation of ion channel function are only starting to emerge.…”