Direct binding of phosphatidylglycerol at specific sites modulates desensitization of a ligand-gated ion channel

Elife. 2019 Nov 14:8:e50766. doi: 10.7554/eLife.50766.


Pentameric ligand-gated ion channels (pLGICs) are essential determinants of synaptic transmission, and are modulated by specific lipids including anionic phospholipids. The exact modulatory effect of anionic phospholipids in pLGICs and the mechanism of this effect are not well understood. Using native mass spectrometry, coarse-grained molecular dynamics simulations and functional assays, we show that the anionic phospholipid, 1-palmitoyl-2-oleoyl phosphatidylglycerol (POPG), preferentially binds to and stabilizes the pLGIC, Erwinia ligand-gated ion channel (ELIC), and decreases ELIC desensitization. Mutations of five arginines located in the interfacial regions of the transmembrane domain (TMD) reduce POPG binding, and a subset of these mutations increase ELIC desensitization. In contrast, a mutation that decreases ELIC desensitization, increases POPG binding. The results support a mechanism by which POPG stabilizes the open state of ELIC relative to the desensitized state by direct binding at specific sites.

Keywords: desensitization; mass spectrometry; membrane channels; molecular biophysics; none; phospholipids; structural biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • DNA Mutational Analysis
  • Ligand-Gated Ion Channels / chemistry
  • Ligand-Gated Ion Channels / genetics
  • Ligand-Gated Ion Channels / metabolism*
  • Mass Spectrometry
  • Molecular Dynamics Simulation
  • Phosphatidylglycerols / metabolism*
  • Protein Binding
  • Protein Conformation
  • Synaptic Transmission


  • Ligand-Gated Ion Channels
  • Phosphatidylglycerols
  • 1-palmitoyl-2-oleoylglycero-3-phosphoglycerol