The dual-gate model for pentameric ligand-gated ion channels activation and desensitization
Abstract
Pentameric ligand-gated ion channels (pLGICs) mediate fast neurotransmission in the nervous system. Their dysfunction is associated with psychiatric, neurological and neurodegenerative disorders such as schizophrenia, epilepsy and Alzheimer's disease. Understanding their biophysical and pharmacological properties, both at the functional and structural levels, thus holds many therapeutic promises. In addition to their agonist-elicited activation, most pLGICs display another key allosteric property, namely desensitization, in which they enter a shut state refractory to activation upon sustained agonist binding. While the activation mechanisms of several pLGICs have been revealed at near-atomic resolution, the structural foundation of desensitization has long remained elusive. Recent structural and functional data now suggest that the activation and desensitization gates are distinct, and are located at both sides of the ion channel. Such a "dual gate mechanism" accounts for the marked allosteric effects of channel blockers, a feature illustrated herein by theoretical kinetics simulations. Comparison with other classes of ligand- and voltage-gated ion channels show that this dual gate mechanism emerges as a common theme for the desensitization and inactivation properties of structurally unrelated ion channels. This article is protected by copyright. All rights reserved.
Keywords
ECD
half maximal effective concentration
EC 50
two-electrode voltage clamp
pLGIC
SAM
silent allosteric modulator
NAM
nicotinic acetylcholine receptors
nAChR
DHA
docosahexaenoic acid
TMD
transmembrane domain
negative allosteric modulator
PAM
TEVC
Abbreviations: 5HT 3 R
5HT 3 serotonin receptor
DAM
extracellular domain
ELIC
Erwinia ligand-gated ion channel
-Aminobutyric acid
GABA A R
GABA A receptor
GlyR
glycine receptor
GLIC
Gloeobacter ligand-gated ion channel
IC 50
pentameric ligand-gated ion channel
positive allosteric modulator
pregnenolone sulfate
half maximal inhibitory concentration
PS
ionotropic glutamate receptor
iGluR
MWC
Monod-Wyman-Changeux
desensitization-modifying allosteric modulator
Origin : Files produced by the author(s)
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