Pentameric ligand-gated ion channels (pLGICs), such as nicotinic acetylcholine, glycine, γ-aminobutyric acid GABA(A/C) receptors, and the Gloeobacter violaceus ligand-gated ion channel (GLIC), are receptors that contain multiple allosteric binding sites for a variety of therapeutics, including general anesthetics. Here, we report the x-ray crystal structure of the Erwinia chrysanthemi ligand-gated ion channel (ELIC) in complex with a derivative of chloroform, which reveals important features of anesthetic recognition, involving multiple binding at three different sites. One site is located in the channel pore and equates with a noncompetitive inhibitor site found in many pLGICs. A second transmembrane site is novel and is located in the lower part of the transmembrane domain, at an interface formed between adjacent subunits. A third site is also novel and is located in the extracellular domain in a hydrophobic pocket between the β7-β10 strands. Together, these results extend our understanding of pLGIC modulation and reveal several specific binding interactions that may contribute to modulator recognition, further substantiating a multisite model of allosteric modulation in this family of ion channels.
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http://dx.doi.org/10.1074/jbc.M112.424507 | DOI Listing |
Korean J Physiol Pharmacol
December 2024
Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
Olanzapine, an atypical antipsychotic, is widely used in the treatment of schizophrenia and bipolar disorder due to its modulation of dopamine and serotonin receptor systems. While its primary action involves antagonism of dopamine D2 and serotonin 5-HT (5-hydroxytryptamine)A receptors, recent evidence suggests that olanzapine also inhibits 5-HT receptors, which are ligand-gated ion channels involved in synaptic transmission in central and peripheral nervous systems. The present study aimed to investigate the action of olanzapine on 5-HT receptor-mediated currents using whole-cell voltage-clamp recordings in NCB-20 neuroblastoma cells.
View Article and Find Full Text PDFKorean J Physiol Pharmacol
December 2024
Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
The 5-hydroxytryptamine type (5-HT) receptor, a ligand-gated ion channel, plays a critical role in synaptic transmission. It has been implicated in various neuropsychiatric disorders. This study aimed to elucidate the mechanism by which quetiapine, an atypical antipsychotic, could inhibit 5-HT receptor-mediated currents in NCB20 neuroblastoma cells.
View Article and Find Full Text PDFBrain Behav Immun
December 2024
School of Basic Medicine, Gannan Medical University, Ganzhou, PR China.
Psychological stress can lead to emotional disorders, such as anxiety and depression; however, the underlying mechanisms are complicated and remain unclear. In this study, we established a mouse psychological stress model using an improved communication box, in which the psychologically stressed mice received visual, auditory, and olfactory emotional stimuli from the mice receiving electric foot shock, thus avoiding physical stress interference. After the 14-day psychological stress paradigm, our mice exhibited a significant increase in depressive and anxious behaviors.
View Article and Find Full Text PDFJ Biol Chem
December 2024
Michael Sars Centre, University of Bergen, Bergen, Norway. Electronic address:
Diarylamidines are a group of widely used small molecule drugs. One common use of diarylamidines is their pharmacological inhibition of ligand-gated cation channels, including tetrameric ionotropic glutamate receptors and trimeric degenerin/epithelial sodium channel channel/acid-sensing ion channels (DEG/ENaC/ASICs). Here, we discover a DEG/ENaC/ASIC channel from the brachiopod (lamp shell) Novocrania anomala, at which diarylamidines act as agonists.
View Article and Find Full Text PDFAnal Chem
December 2024
College of Chemistry and Materials Science, Guangdong Provincial Key Laboratory of Speed Capability Research, Su Bingtian Center for Speed Research and Training, Jinan University, Guangzhou 510632, China.
The process of "reading" and "writing" in biomemory involves the transmission of electrical signals between neurons, with ligand-gated ion channels assuming a key role. The solid-state nanochannels exhibit certain similarities with neurons. Information transmission can be achieved by controlling the flow of ions within nanochannels, rendering them potentially suitable for simulating neuron behavior.
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