Intracellular Passage Of Na+ In An Active State G Protein Coupled Receptor

Abstract

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.