Characterization of an open-channel structure and lateral conduction pathway in the cation-selective pentameric ligand-gated ion channel, ELIC

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Abstract
Open-channel structures of multiple pentameric ligand-gated ion channels (pLGICs) have been determined, including the prokaryotic model pLGIC, Erwinia ligand-gated ion channel (ELIC). For many of these structures, it remains uncertain whether they represent a physiologic open-channel state because the conditions used for structure determination do not match those of functional measurements in cell membranes. Here, MD simulation is used to examine the ion conduction properties of the ELIC open-channel structure, which was determined using a non-desensitizing mutant called ELIC5. Results from simulations show that the pore remains stably open on the microsecond timescale, but computational electrophysiology measurements demonstrate a large outward rectification and an inward conductance that is significantly lower than experiment. This discrepancy is attributed to a constricted extracellular domain (ECD), which restricts the passage of ions between the ECD vestibule and extracellular solution. Unbiased MD simulation of the ELIC5 structure demonstrates spontaneous widening of an intersubunit space in the ECD to expose a lateral fenestration, which becomes the dominant ion conduction pathway. Computational electrophysiology of the ELIC5 MD-refined structures with a widened lateral fenestration shows better agreement with experimental single-channel recordings. Mutations of residues along the lateral ion conduction pathway show reduced single-channel conductance, supporting the importance of the lateral fenestration for ion conduction in a cation-selective pLGIC.
Funding Information
  • National Institutes of Health (K08GM152844)
  • National Institutes of Health (R35-GM137597)
  • National Science Foundation (DGE 2152059)
  • National Science Foundation (#2138259)
  • National Science Foundation (#2138286)
  • National Science Foundation (#2138307)
  • National Science Foundation (#2137603)
  • National Science Foundation (#2138296)
  • Agence Nationale de la Recherche (ANR-11-LABX-0011)
  • Foundation for Anesthesia Education and Research (MRTG-0215-2022-Arcario)
  • Advanced Cyberinfrastructure Coordination Ecosystem: Services & Support

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