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.

Keywords: allosteric modulation; annular; lipid binding sites; lipid–protein interactions; non-annular; pentameric ligand-gated ion channels.

Figure 1

pLGICs display a conserved core architecture with diverse auxiliary features. Side views of the prokaryote DeCLIC (PDB: 6V4S, far left), the human α1β3γ2 GABA_AR (PDB: 7QNE, middle left), and the Torpedo nAChR (PDB: 7QL5, middle right) colored according to domains (NTD, orange; ECD, red; TMD, blue; ICD, green). Bound agonists are presented as cyan spheres at the interfaces between two subunits. In the side views, the principal subunit is on the left and the complementary subunit is on the right. Residues forming the channel gate are presented as tan spheres. Top-down views of the Torpedo nAChR ECD (top) and TMD (bottom) are shown on the far right colored according to subunit (α, red; β, blue; γ, purple; δ, green).

Figure 2

Lipid binding to both extracellular and intracellular leaflet sites on the nAChR. Side views of the TMD for the cholesterol-bound α3β4 nAChR (PDB: 6PV7, far left) and α7 nAChR (PDB: 7EKI, middle left), phospholipid-bound Torpedo nAChR (PDB: 7QL5, middle right), and cholesterol- and phospholipid-bound Torpedo nAChR (PDB: 7SMQ, far right) represented as surfaces, with principal and complementary subunits colored in pink and blue, respectively. Bound cholesterol (brown) and phospholipids (yellow) are presented as spheres with oxygen, nitrogen, and phosphorus colored in red, blue, and orange, respectively.

Figure 3

Cholesterol and phospholipids bind to adjacent or overlapping sites in Torpedo nAChR structures. Zoomed in views (defined in Figure 2) of Torpedo nAChR structures with bound phospholipids (PDB: 7QL5) or both phospholipids and cholesterol (PDB: 7SMQ). Subunits and lipids are colored as in Figure 2, with residues interacting with bound lipids represented as sticks colored according to residue type (non-polar, tan; aromatic, yellow; polar, green; cationic, blue; anionic, red). The M2–M4 salt bridge adjacent to the bound lipids is shown as a dashed line.

Figure 4

PIP₂ binds to a highly coordinated site in the α1β3γ2 GABA_AR. Side view of the α1β3γ2 GABA_AR TMD (PDB: 7QNE) shown on the left as surface, with a zoomed in view of the boxed region highlighting PIP₂ and its coordinating residues (colored as residue-type, with positively charged residues colored in blue and neutral hydrogen bonding residues colored in green) represented as sticks on the right. The bound PIP₂ lipid is colored as in Figure 2, with dashed lines indicating residue-mediated coordination of the head group phosphates. A 90° rotated view is shown on the extreme right to delineate coordinating residues.

Figure 5

GlyR structures display an annular layer of lipid acyl chains around the perimeter of the TMD. Side views of the detergent-solubilized native porcine GlyR (PDB: 7MLY, far left), GABA-bound SMA-solubilized α1 GlyR (PDB: 6PLU, middle left), taurine-bound SMA-solubilized α1 GlyR in a closed state (PDB: 6PLU, middle right) and taurine-bound SMA-solubilized α1 GlyR in a desensitized state (PDB: 6PLS, far right) with diffuse density corresponding to lipid acyl chains shown as yellow spheres.

Figure 6

Phospholipid and cardiolipin binding to ELIC. Side view of the ELIC TMD (PDB: 7L6Q) represented as surface with the principal and complementary subunits colored in pink and blue, respectively, and bound cardiolipin and PG shown as spheres (center). Zoomed in views of the bound cardiolipin and PG are shown on the left and right, respectively, with coordinating residues represented as sticks, with basic residues colored in blue, aromatic residues in yellow, polar residues in green and proline in tan.