Asymmetric opening of the homopentameric 5-HT3A serotonin receptor in lipid bilayers

Yingyi Zhang,Rongfeng Zou,Harald Köfeler,Martina Zandl-Lang,Ricardo M. Sanchez,Mikhail Kudryashev,Patricia M. Dijkman,Shuguang Yuan,Horst Vogel,Luise Eckhardt-Strelau

doi:10.1038/s41467-021-21016-7

Abstract

Pentameric ligand-gated ion channels (pLGICs) of the Cys-loop receptor family are key players in fast signal transduction throughout the nervous system. They have been shown to be modulated by the lipid environment, however the underlying mechanism is not well understood. We report three structures of the Cys-loop 5-HT3A serotonin receptor (5HT3R) reconstituted into saposin-based lipid bilayer discs: a symmetric and an asymmetric apo state, and an asymmetric agonist-bound state. In comparison to previously published 5HT3R conformations in detergent, the lipid bilayer stabilises the receptor in a more tightly packed, ‘coupled’ state, involving a cluster of highly conserved residues. In consequence, the agonist-bound receptor conformation adopts a wide-open pore capable of conducting sodium ions in unbiased molecular dynamics (MD) simulations. Taken together, we provide a structural basis for the modulation of 5HT3R by the membrane environment, and a model for asymmetric activation of the receptor.

Highlights

Pentameric ligand-gated ion channels of the Cys-loop receptor family are key players in fast signal transduction throughout the nervous system
Based on the data presented here and a previous functional study[29], we propose a hypothetical model for allosterically lipidmodulated asymmetric activation of 5-HT3A serotonin receptor (5HT3R) upon serotonin binding (Fig. 9)
Considering the highly similar conformation of the extracellular domain (ECD) of the different subunits, there is no clear chemical determinant for the asymmetry observed in the transmembrane domain (TMD) of the fully ligand-bound serotonin-5HT3R-Salipro form

Summary

Introduction

Pentameric ligand-gated ion channels (pLGICs) of the Cys-loop receptor family are key players in fast signal transduction throughout the nervous system They have been shown to be modulated by the lipid environment, the underlying mechanism is not well understood. Besides being a therapeutic target[14], the 5HT3R represents an interesting case as despite several structures having been reported for the receptor in detergent in the presence and absence of agonist[15,16,17,18], the mechanism of gating remains an open question[19] This is in part due to difficulties in unambiguously assigning functional states to static structures and the notable differences observed between the structures of the serotonin-bound receptor in detergent micelles[17,18]. Our results provide a structural basis for the modulation of 5HT3R activity by the lipid membrane environment and broaden our understanding of 5HT3R gating

Methods

Results

Conclusion