Internal Sodium in GPCRs Strongly Responds to Transmembrane Voltage Changes

摘要: G protein-coupled receptors (GPCRs) are the largest superfamily of membrane proteins in human genome, mediating propagation extracellular ligand binding information into intracellular signal transduction cascades. Crystal structures have revealed a water-filled hydrophilic internal pocket within their transmembrane domain, extending from orthosteric ligand-binding site to regions near protein site. Recent high-resolution identified sodium ion base this pocket, coordinated by highly conserved residues (1,2). Owing conservation level, may play role for most rhodopsin-like GPCRs (3). Recently, functional or conformational effects been shown be elicited physiological voltage several GPCRs, and voltage-clamp recordings determined gating charge ∼0.85 e M1 M2 muscarinic (4). However, nature sensor has remained enigmatic. Here we show MD computational electrophysiology simulations (5) that delta-opioid is mobile under influence changes. By calculating energetics movement along axis, find free energy barriers migration can overcome range. Furthermore, demonstrate motion axis creates excellent agreement with experimentally measured currents. Thus, voltage-induced movements Na+ represent an attractive mechanism voltage-regulation GPCRs.1. Liu, W. et al., Science 337: 232-236, 2012.2. Fenalti, G. Nature 506: 191-196, 2014.3.Katritch, V. TiBS 39: 233-244, 2014.4. Ben-Chaim, Y. 444: 106-9, 2006.5. Kutzner, C. Biophysical Journal 101: 809-817, 2011.