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

Abstract

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.

Regulation of Gramicidin Channel Function Solely by Changes in Lipid Intrinsic Curvature

“…Though membrane proteins can be regulated by maneuvers that change the lipid bilayer thickness and intrinsic curvature ( Andersen and Koeppe, 2007 ), more specific lipid-protein interactions will be important as well ( Lee, 2003 , 2004 ; Marsh, 2008 ; Landreh et al, 2016 ; Henault et al, 2019 ; Cheng et al, 2022 ), with the prime example being the regulation of many different channels by phosphoinositides ( Huang et al, 1998 ; Hilgemann et al, 2001 , 2018 ; Hansen et al, 2011 ; Logothetis et al, 2015 ). Given the chemical heterogeneity of biological membranes ( Symons et al, 2021 ), and the range of lipid specificities of integral membrane proteins ( Marsh and Pali, 2004 ), the challenge becomes to define the relative importance of the more general bilayer and more specific lipid contributions to the free energy difference between different protein conformations, i.e., to the regulation of membrane protein function.…”

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“…The binding sites of MscL agonists thus far are not only consistently seen toward the cytoplasmic–membrane interface but also consistently observed at the interface of assembled subunits. Such binding at subunit interfaces was first described for the nicotinic acetylcholine receptor in 1989 [ 42 ] and has since been observed for many ligands of several channels [ 43 ].…”

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