Lipid-dependent gating of ion channels

Ion channels are important because all live cells rely on them to establish a transmembrane electrostatic potential and ion gradients across their membranes. They all are integrated inside lipid bilayers and form ion conducting pores whose open states allow passive flow of certain ions down their electrochemical gradients. The dissipative flow of ions usually sends a signal at the cost of cell's energy. In general, ion channels face two aqueous phases and a lipid phase. Via chemical interactions through physical contact, ion channels can sense changes in all three phases. Ion channels are good model systems for studying lipid-channel interactions because patch-clamp recordings of single or multiple channels can be made even though manipulation of lipids immediately around ion channels is difficult to achieve. Based on the effective distance of chemical forces and the physical size of lipids, the first layer of lipid molecules, called the annular lipids, next to the transmembrane domain of a channel dominates the lipid-protein interaction. We propose that the annular lipids and the channel form a functional unit and the former need to rearrange in company with the allosteric conformational change in the latter. The exchange of lipids between the annular layer and the bulk lipid phase is therefore an important factor. In consideration of the chemical interactions, there are specific interaction sites for specific lipid molecules on proteins through induced-fit, which have sub-mM or higher affinity and could be stereo-specific. Low affinity binding sites are often nonspecific and may be less sensitive to the stereo-chemistry of the lipids. Lipid-dependent gating of voltage-gated ion channels refers to channel's sensitivity to the chemical differences between phospholipids and nonphospholipids. The presence or absence of phosphate groups causes a major chemical difference in charge density and H-bonding network such that the energetic differences of a channel protein between the open and closed states may become sufficiently significant in the two groups of lipids. In this chapter, we will focus on the prior studies that demonstrated significant lipid-dependent gating effects on ion channels, and present a systematic thermodynamic description, which may be suitable to explaining many, if not all, of the prior observations. We will discuss the current technical difficulties in studying the lipid-dependent gating and possible solutions in addressing them in the future.