Vestibular modulation by stimulant derivatives in a pentameric ligand‐gated ion channel
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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.
Experimental Approach
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.
Key Results
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.
Conclusions and Implications
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.
