Download MendeleyVestibular modulation by stimulant derivatives in a pentameric ligand-gated ion channel.
Karlsson, E., Anden, O., Fan, C., Fourati, Z., Haouz, A., Zhuang, Y., Howard, R.J., Delarue, M., Lindahl, E.(2025) Br J Pharmacol
- PubMed: 40065647
- DOI: https://doi.org/10.1111/bph.70011
- Primary Citation of Related Structures:
9EWA, 9EWL, 9EX4, 9EX6, 9F5N, 9F5O - PubMed Abstract:
Allosteric modulation of pentameric ligand-gated ion channels (pLGICs) are critical for the action of neurotransmitters and many psychoactive drugs. However, details of their modulatory mechanisms remain unclear, especially beyond the orthosteric neurotransmitter-binding sites. The recently reported prokaryotic symbiont of Tevnia jerichonana ligand-gated ion channel (sTeLIC), a pH-gated homologue of eukaryotic receptors in the pLGIC family, is thought to be modulated by aromatic compounds via a relatively uncharacterised modulatory site in the extracellular vestibule. We have characterised the effects of psychostimulant derivatives on sTeLIC using two-electrode voltage-clamp electrophysiology in the presence and absence of engineered mutations, and determined X-ray and cryo-EM structures of the channel in both closed and open states. We have shown that sTeLIC is sensitive to potentiation by several amphiphilic compounds, which preferentially bind to a vestibular pocket in the contracted open-state extracellular domain. This work provides a detailed structure-function mechanism for allosteric potentiation via a noncanonical ligand site, with potential conservation of the eukaryotic pentameric ligand-gated ion channels.
Organizational Affiliation:
Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, Solna, Sweden.
