PT  - JOURNAL ARTICLE
AU  - Owen N. Vickery
AU  - Catarina A. Carvalheda
AU  - Saheem A. Zaidi
AU  - Andrei V. Pisliakov
AU  - Vsevolod Katritch
AU  - Ulrich Zachariae
TI  - Intracellular passage of Na<sup>+</sup> in an active state g-protein coupled receptor
AID  - 10.1101/124420
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 124420
4099  - http://biorxiv.org/content/early/2017/07/21/124420.short
4100  - http://biorxiv.org/content/early/2017/07/21/124420.full
AB  - Playing a central role in cell signalling, GPCRs have evolved into 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. High resolution structural studies have recently revealed that inactive class-A GPCRs harbour a conserved binding site for Na+ ions in the centre 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, which locks receptors in long-lived active-state conformations.