Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels

Lipids modulate the function of many ion channels, possibly through direct lipid-protein interactions. The recent outpouring of ion channel structures by cryo-EM has revealed many lipid binding sites. Whether these sites mediate lipid modulation of ion channel function is not firmly established in most cases. However, it is intriguing that many of these lipid binding sites are also known sites for other allosteric modulators or drugs, supporting the notion that lipids act as endogenous allosteric modulators through these sites. Here, we review such lipid-drug binding sites, focusing on pentameric ligand-gated ion channels and transient receptor potential channels. Notable examples include sites for phospholipids and sterols that are shared by anesthetics and vanilloids. We discuss some implications of lipid binding at these sites including the possibility that lipids can alter drug potency or that understanding protein-lipid interactions can guide drug design. Structures are only the first step toward understanding the mechanism of lipid modulation at these sites. Looking forward, we identify knowledge gaps in the field and approaches to address them. These include defining the effects of lipids on channel function in reconstituted systems using asymmetric membranes and measuring lipid binding affinities at specific sites using native mass spectrometry, fluorescence binding assays, and computational approaches.

Automated summary

Lipids modulate the function of ion channels through direct lipid-protein interactions. Cryo-EM studies have identified lipid binding sites on ion channels, but the role of these sites in lipid modulation is not fully understood. These binding sites also coincide with sites for other allosteric modulators or drugs, suggesting that lipids act as endogenous allosteric modulators. This review focuses on lipid-drug binding sites in pentameric ligand-gated ion channels and transient receptor potential channels, highlighting the shared sites for phospholipids, sterols, anesthetics, and vanilloids. The implications of lipid binding at these sites, such as potential changes in drug potency and guiding drug design through protein-lipid interactions, are discussed. However, further studies are needed to fully understand the mechanisms of lipid modulation at these sites.