Abstract
GLIC receptor is a bacterial pentameric ligand-gated ion channel whose action is inhibited by xenon. Xenon has been used in clinical practice as a potent gaseous anaesthetic for decades, but the molecular mechanism of interactions with its integral membrane receptor targets remains poorly understood. Here we characterize by X-ray crystallography the xenon-binding sites within both the open and “locally-closed” (inactive) conformations of GLIC. Major binding sites of xenon, which differ between the two conformations, were identified in three distinct regions that all belong to the trans-membrane domain of GLIC: 1) in an intra-subunit cavity, 2) at the interface between adjacent subunits, and 3) in the pore. The pore site is unique to the locally-closed form where the binding of xenon effectively seals the channel. A putative mechanism of the inhibition of GLIC by xenon is proposed, which might be extended to other pentameric cationic ligand-gated ion channels.
Highlights
Gaseous anesthetics like xenon (Xe) and nitrous oxide (N2O) have been used in clinical practice for decades
To improve the understanding of molecular interactions between xenon and transmembrane receptor targets, we investigated xenon binding with the Gloebacter violaceus ligandgated ion channel (GLIC), a member of the pentameric ligand-gated ion channels (pLGICs) family, using X-ray crystallography under pressurized gas
Xenon-bound GLIC open and LC structures were obtained from crystals pressurized with 2 MPa (20 bar) of xenon and analysed by X-ray crystallography at 3.1 and 3.4 Å resolution respectively (Table 1)
Summary
Gaseous anesthetics like xenon (Xe) and nitrous oxide (N2O) have been used in clinical practice for decades. The main interest of xenon resides in its remarkably safe clinical profile with a rapid pulmonary uptake and elimination, no hepatic or renal metabolism. It readily crosses the blood brain barrier and has a low solubility in blood, which is advantageous in terms of rapid inflow and washout [2, 4, 5]. Xenon targets several neuronal receptors, such as the N-methyl-D-aspartate (NMDA) glutamatergic receptor [13] and the TREK-1 two-pore domain K+ channel [14]. Xenon alters neuronal excitability by modulating agonist responses of cationic pentameric ligand-gated ion channels (pLGICs). Xenon inhibits the excitatory cationic nicotinic acetyl-choline (nAChR) receptor [15, 16] while it has a minimal effect on inhibitory anionic γ-amino-butyric type-A receptor (GABAAR) [17,18,19,20]
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