Intracellular Transfer of Na+ in an Active State G Protein Coupled Receptor

Owen Vickery, Catarina Carvalheda Dos Santos, Saheem A. Zaidi, Andrei Pisliakov, Vsevolod Katritch, Ulrich Zachariae (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)
130 Downloads (Pure)


Playing a central role in cell signaling, G-protein-coupled receptors (GPCRs) are the largest superfamily of membrane proteins and form the majority of drug targets in humans. How extracellular agonist binding triggers the activation of GPCRs and associated intracellular effector proteins remains, however, poorly understood. Structural studies have revealed that inactive class A GPCRs harbor a conserved binding site for Na+ ions in the center of their transmembrane domain, accessible from the extracellular space. Here, we show that the opening of a conserved hydrated channel in the activated state receptors allows the Na+ ion to egress from its binding site into the cytosol. Coupled with protonation changes, this ion movement occurs without significant energy barriers, and can be driven by physiological transmembrane ion and voltage gradients. We propose that Na+ ion exchange with the cytosol is a key step in GPCR activation. Further, we hypothesize that this transition locks receptors in long-lived active-state conformations. Vickery et al. present molecular dynamics simulations and free energy calculations, which suggest that a key step in class A GPCR activation is the exchange of a Na+ ion from an extracellular binding pocket to the cytoplasm.

Original languageEnglish
Pages (from-to)171-180.e2
Number of pages12
Issue number1
Early online date14 Dec 2017
Publication statusPublished - 2 Jan 2018


  • free energy profiles
  • GPCR
  • GPCR activation
  • ion channels
  • membrane surface receptors
  • pK
  • polar network
  • protonation state
  • signal transduction
  • sodium
  • Humans
  • Cations, Monovalent
  • Thermodynamics
  • Ion Transport
  • Protein Interaction Domains and Motifs
  • Binding Sites
  • Protein Conformation, alpha-Helical
  • Static Electricity
  • Molecular Dynamics Simulation
  • Amino Acid Motifs
  • Receptor, Muscarinic M2/chemistry
  • Sodium/chemistry
  • Carbachol/chemistry
  • Phosphatidylcholines/chemistry
  • Hydrophobic and Hydrophilic Interactions
  • Protein Binding
  • Ligands
  • Kinetics
  • Ion Channel Gating


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