Vestibular Modulation by Stimulant Derivatives in a Pentameric Ligand-Gated Ion Channel

Author:

Karlsson Emelia,Andén Olivia,Fan Chen,Fourati ZainebORCID,Haouz Ahmed,Zhuang YuxuanORCID,Howard Rebecca JORCID,Delarue MarcORCID,Lindahl ErikORCID

Abstract

AbstractAllosteric modulation of pentameric ligand-gated ion channels (pLGICs) is critical to 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 channel sTeLIC, a pH-gated homolog of eukaryotic receptors in the pLGIC family, is thought to be modulated by aromatic compounds via a relatively uncharacterized modulatory site in the extracellular vestibule. Here, we show that sTeLIC is sensitive to potentiation by psychostimulant derivatives. By determining new cryo-EM and X-ray structures in closed and open states, and testing the impact of targeted mutations on electrophysiological behavior, we show that several amphiphilic compounds preferentially bind a vestibular pocket in the contracted open-state extracellular domain. This work provides a detailed structure-function mechanism for allosteric potentiation via a noncanonical lig- and site, with potential conservation in eukaryotic pentameric ligand-gated ion channels.

Publisher

Cold Spring Harbor Laboratory

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