Recent Insight into Lipid Binding and Lipid Modulation of Pentameric Ligand-Gated Ion Channels

Abstract

Pentameric ligand-gated ion channels (pLGICs) play a leading role in synaptic communication, are implicated in a variety of neurological processes, and are important targets for the treatment of neurological and neuromuscular disorders. Endogenous lipids and lipophilic compounds are potent modulators of pLGIC function and may help shape synaptic communication. Increasing structural and biophysical data reveal sites for lipid binding to pLGICs. Here, we update our evolving understanding of pLGIC–lipid interactions highlighting newly identified modes of lipid binding along with the mechanistic understanding derived from the new structural data.

Open-channel structure of a pentameric ligand-gated ion channel reveals a mechanism of leaflet-specific phospholipid modulation

“…With the recent abundance of lipid-bound pLGIC structures by cryo-EM, investigation into the structural mechanisms of lipid modulation has focused on direct binding of lipids to specific sites 12,13,15,[17][18][19][20][21][22] . Structures of the 5-HT 3A receptor (5-HT 3A R), GABA A receptor, nAchR and the prototypic pLGICs, Erwinia chrysanthemi ligand-gated ion channel (ELIC) and Gloeobacter violaceus ligand-gated ion channel (GLIC), show bound phospholipids at various sites 14,19,[23][24][25][26][27][28] .…”

Studying Membrane Protein–Lipid Specificity through Direct Native Mass Spectrometric Analysis from Tunable Proteoliposomes

“…This not only enables the detection of the membrane-embedded organization state but also enables us to titrate in/out specific membrane constituents/properties to tease apart their role in regulating the observed oligomeric organization states. Such customizability of liposomes to mimic and modulate properties of the native membrane has already made it the vehicle of choice to study a range of functions of membrane proteins, including ion transport, , G-protein driven signaling, , and protein trafficking, , to name a few. Very recently, there has also been a steady increase in the number of CryoEM structures of membrane proteins directly from liposomes. − Coupling these techniques with our liposome-nMS protocol will allow direct structural, functional, and mass spectral analysis of target membrane proteins directly from the same liposome samples.…”

“…6−8 From inducing specific functional conformational states of ion channels to regulating functional homomeric and heteromeric assemblies, there are abundant examples of this direct interaction. [2][3][4]6,9 In these cases, lipids act like endogenous ligands and modulate the structural and functional states of the protein through direct and specific binding. Alternatively, cells also organize their lipidome in a laterally heterogeneous manner to create membrane nanodomains that harbor specific biophysical properties such as membrane curvature, fluidity, tension, and so on.…”

“…This chemical interplay between proteins and lipids can be broadly classified into two categories. In certain cases, specific lipids can directly bind to a target protein in a distinct binding site and regulate its conformational state, functional assemblies, − or its ability to interact with downstream effector proteins. − From inducing specific functional conformational states of ion channels to regulating functional homomeric and heteromeric assemblies, there are abundant examples of this direct interaction. − ,, In these cases, lipids act like endogenous ligands and modulate the structural and functional states of the protein through direct and specific binding. Alternatively, cells also organize their lipidome in a laterally heterogeneous manner to create membrane nanodomains that harbor specific biophysical properties such as membrane curvature, fluidity, tension, and so on. ,− These bulk bilayer properties also can directly modulate all aspects of biogenesis, the assembly state, and functions of membrane proteins.…”

Multiscale molecular dynamics simulations predict arachidonic acid binding sites in human ASIC1a and ASIC3 transmembrane domains

“…The neuronal membrane environment plays an important role in the function of ion channels. For example, pentameric ligand-gated ion channels, such as the nicotinic acetylcholine receptors, are functionally sensitive to the lipid composition of their surrounding membrane ( Baenziger et al, 2000 ; daCosta et al, 2013 ; Ananchenko et al, 2022 ). It has also been shown that several voltage-gated ion channels are functionally affected by polyunsaturated fatty acids (PUFAs), with the presence of PUFAs altering the voltage dependence and maximal current of these channels ( Elinder and Liin, 2017 ; Tong et al, 2019 ).…”