Vestibular modulation by stimulant derivatives in a pentameric ligand-gated ion channel.

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Tác giả: Olivia Andén, Marc Delarue, Chen Fan, Zaineb Fourati, Ahmed Haouz, Rebecca J Howard, Emelia Karlsson, Erik Lindahl, Yuxuan Zhuang

Ngôn ngữ: eng

Ký hiệu phân loại:

Thông tin xuất bản: England : British journal of pharmacology , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 686852

BACKGROUND AND PURPOSE: 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.
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