Differential interactions of resting, activated, and desensitized states of the α7 nicotinic acetylcholine receptor with lipidic modulators

Yuxuan Zhuang, Colleen M. Noviello, Ryan E. Hibbs, Rebecca J. Howard, Erik Lindahl

Research output: Contribution to journalArticlepeer-review

Abstract

The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that modulates neuronal excitability, largely by allowing Ca2+ permeation. Agonist binding promotes transition from a resting state to an activated state, and then rapidly to a desensitized state. Recently, cryogenic electron microscopy (cryo-EM) structures of the human α7 receptor in nanodiscs were reported in multiple conformations. These were selectively stabilized by inhibitory, activating, or potentiating compounds. However, the functional annotation of these structures and their differential interactions with unresolved lipids and ligands remain incomplete. Here, we characterized their ion permeation, membrane interactions, and ligand binding using computational electrophysiology, free-energy calculations, and coarse-grained molecular dynamics. In contrast to nonconductive structures in apparent resting and desensitized states, the structure determined in the presence of the potentiator PNU-120596 was consistent with an activated state permeable to Ca2+. Transition to this state was associated with compression and rearrangement of the membrane, particularly in the vicinity of the peripheral MX helix. An intersubunit transmembrane site was implicated in selective binding of either PNU-120596 in the activated state or cholesterol in the desensitized state. This substantiates functional assignment of all three lipid-embedded α7-receptor structures with ion-permeation simulations. It also proposes testable models of their state-dependent interactions with lipophilic ligands, including a mechanism for allosteric modulation at the transmembrane subunit interface.

Original languageEnglish (US)
Pages (from-to)e2208081119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number43
DOIs
StatePublished - Oct 25 2022

Keywords

  • cholesterol
  • coarse-grained simulations
  • computational electrophysiology
  • ligand-gated ion channel
  • nicotinic acetylcholine receptor

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Differential interactions of resting, activated, and desensitized states of the α7 nicotinic acetylcholine receptor with lipidic modulators'. Together they form a unique fingerprint.

Cite this