What is it about?
We studied how a proton‑activated pentameric ligand‑gated ion channel (GLIC) passes messages from its “sensor” on the outside (the extracellular domain) to its “gate” in the membrane (the transmembrane pore). Using atomistic molecular dynamics and dynamic network analysis, we mapped five main communication pathways—via the Cys loop, the β1–β2 loop, pre‑M1/M1, and two loop‑F intersubunit routes—that link ligand/proton binding to pore opening or closing. These pathways change with pH and with the channel’s conformational state (open, closed, and locally closed).
Featured Image
Photo by GuerrillaBuzz on Unsplash
Why is it important?
Pentameric ligand‑gated ion channels control synaptic signaling and are targets for anesthetics and neuromodulatory drugs. Knowing the specific routes that relay signals from binding sites to the pore helps explain how mutations disrupt function and how small molecules can modulate gating. Our state‑dependent maps highlight conserved communication networks likely shared across the superfamily, providing concrete handles for rational drug design and for interpreting disease‑linked variants.
Perspectives
• Therapeutics: Target residues along the dominant pathways (e.g., Cys loop, β1–β2 loop, pre‑M1/M1) to fine‑tune gating efficacy or bias specific states. • Mutations and disease: Use the pathway maps to predict which variants break communication (e.g., D32–R192 salt bridge) and how to rescue them. • Mechanistic generalization: Test conservation of these networks in human pLGICs (GABA_A, GlyR, nAChR, 5‑HT_3_) with state‑resolved simulations and experiments. • Methodology: Combine enhanced sampling with network analysis to capture full gating transitions and quantify pathway switching under different ligands. • Design: Explore anesthetic and allosteric modulator binding near pre‑M1/M1 and loop‑F interfaces to steer communication rather than just block the pore.
Dr Marc Baaden
CNRS
Read the Original
This page is a summary of: State-Dependent Dynamic Communication Networks in a Pentameric Ligand-Gated Ion Channel, The Journal of Physical Chemistry, September 2025, American Chemical Society (ACS),
DOI: 10.1021/acs.jpcb.5c03991.
You can read the full text:
Resources
Contributors
The following have contributed to this page
