Abstract：
BACKGROUND AND PURPOSE:GABAA receptors mediate neuronal inhibition in the brain. They are the primary targets for benzodiazepines, which are widely used to treat neurological disorders including anxiety, epilepsy and insomnia. The mechanism by which benzodiazepines enhance GABAA receptor activity has been extensively studied, but there is little mechanistic information on how non-benzodiazepine drugs that bind to the same site exert their effects. Eszopiclone and zolpidem are two non-benzodiazepine drugs for which no mechanism of action has yet been proposed, despite their clinical importance as sleeping aids. Here we investigate how both drugs enhance the activity of α1β2γ2 GABAA receptors. EXPERIMENTAL APPROACH:We used rapid ligand application onto macropatches and single-channel kinetic analysis to assess rates of current deactivation. We also studied synaptic currents in primary neuronal cultures and in heterosynapses, whereby native GABAergic nerve terminals form synapses with HEK293 cells expressing α1β2γ2 GABAA receptors. Drug binding and modulation was quantified with the aid of an activation mechanism. KEY RESULTS:At the single-channel level, the drugs prolonged the duration of receptor activation, with similar KD values of ∼80 nM. Channel activation was prolonged primarily by increasing the equilibrium constant between two connected shut states that precede channel opening. CONCLUSIONS AND IMPLICATIONS:As the derived mechanism successfully simulated the effects of eszopiclone and zolpidem on ensemble currents, we propose it as the definitive mechanism accounting for the effects of both drugs. Importantly, eszopiclone and zolpidem enhanced GABAA receptor currents via a mechanism that differs from that proposed for benzodiazepines.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Dixon CL,Harrison NL,Lynch JW,Keramidas Adoi
10.1111/bph.13142subject
Has Abstractpub_date
2015-07-01 00:00:00pages
3522-36issue
14eissn
0007-1188issn
1476-5381journal_volume
172pub_type
杂志文章abstract：:1 The concentrations of p- and m-tyramine were measured in the caudate nucleus of the rat brain following subcutaneous injection of reserpine or intraventricular injection of 6-hydroxydopamine, beta-Phenylethylamine was analysed in the hypothalamus after reserpine. 2 Endogenous levels of p-tyramine and m-tyramine in t...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1977.tb06996.x
更新日期：1977-01-01 00:00:00
abstract：:1. A quantitative in vitro study has been made of the actions of glyceryl trinitrate and sodium nitrite on vascular smooth muscle (dog femoral artery and saphenous vein; rat portal vein); these have been compared with the actions of papaverine, isoprenaline, salbutamol, pentaerythritol tetranitrate and trimetazidine. ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1977.tb16760.x
更新日期：1977-05-01 00:00:00
abstract：:We have demonstrated previously that infusion of angiotensin II (AngII) into hyperlipidemic mice augments atherosclerosis and results in the formation of abdominal aortic aneurysms (AAA). The purpose of this study was to determine the role of aldosterone in these AngII-induced vascular pathologies. Male apolipoprotein...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0706098
更新日期：2005-02-01 00:00:00
abstract：:1. We studied the biochemical and contractile responses of isolated human myocardial tissue expressing native receptor variants of the 389G>R beta(1)-adrenoceptor polymorphism. 2. Right atrial appendage was obtained from homozygous RR patients (n=37) and homozygous GG patients (n=17) undergoing elective cardiac surger...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0705030
更新日期：2003-01-01 00:00:00
abstract：:1 A rat isolated gastric mucosal preparation was used to monitor histamine output and acid secretion during stimulation by different secretagogues. 2 In non-stimulated preparations, spontaneous histamine output decreased over 450 min. 3 Stimulation of secretion with 4 (5)-methylhistamine or dibutyryl cyclic adenosine ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1982.tb09190.x
更新日期：1982-05-01 00:00:00
abstract：:In vitro preparations of rabbit heart were made from which measurements of effective refractory period (ERP), atrio-Hisian (A-H) and His-Purkinje (H-P) conduction times could be obtained, analogous to electrophysiological measurements customarily carried out in vivo. Intracellular potentials also were recorded from th...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1983.tb10007.x
更新日期：1983-07-01 00:00:00
abstract：:The human distal gut is home to a rich and dense microbial community with representatives of all three domains of life which are intricately connected with our physiology and health. The combined genomes of these microbes, collectively called the human microbiome, vastly expand the metabolic capacities of our own geno...
journal_title：British journal of pharmacology
pub_type： 杂志文章,评审
doi：10.1111/bph.14085
更新日期：2018-12-01 00:00:00
abstract：:1. The effects of bretylium were investigated on purified Na,K-ATPase from guinea-pig heart and on the Na/K pump in trout erythrocytes, with a view to further identifying the mechanism(s) associated with its antiarrhythmic effects. 2. Na,K-ATPase activity of the thiocyanate-dispersed enzyme was determined by the measu...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1991.tb12523.x
更新日期：1991-12-01 00:00:00
abstract：BACKGROUND AND PURPOSE:We have previously shown that lipid mediators, produced by phospholipase D and C, are generated in OX(1) orexin receptor signalling with high potency, and presumably mediate some of the physiological responses to orexin. In this study, we investigated whether the ubiquitous phospholipase A(2) (PL...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.2009.00535.x
更新日期：2010-01-01 00:00:00
abstract：:1. Sigma (sigma) receptors have generated a great deal of interest on the basis of their possible roles in various pathologies, including cytoprotection. Although the exact function of sigma-1 (sigma(1)) receptors is not yet known, their role in the regulation of intracellular Ca(2+) levels and sterol biosynthesis, fu...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0704626
更新日期：2002-04-01 00:00:00
abstract：:Sodium transport has been measured in the isolated epithelium from colons of male Sprague-Dawley rats. Sodium transport in colons was induced by pretreating the animals with dexamethasone (6 mg kg-1) which caused the appearance of an amiloride-sensitive short circuit current within a few hours. Forskolin, a diterpene,...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1983.tb10017.x
更新日期：1983-07-01 00:00:00
abstract：:(1) We determined the effects of long-term treatment with aminoguanidine (AG), an inhibitor of advanced glycation end products, on the mechanical properties of the arterial system in aged Fisher 344 rats, using the aortic impedance analysis. (2) Normotensive rats were treated from 18 to 24 months with AG (1 g/l-1 in d...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0705410
更新日期：2003-09-01 00:00:00
abstract：:1. The influence of feeding 2 levels of sotalol on the incidence of beta-aminopropionitrile (BAPN)-induced aortic ruptures of immature turkeys was determined.2. Four of 22 turkeys fed 0.12% sotalol and 0.07% BAPN died of aortic ruptures, but 6 of 21 turkeys fed only BAPN died of the syndrome.3. Blood pressure, heart r...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1972.tb08095.x
更新日期：1972-07-01 00:00:00
abstract：:1. The effects of capsaicin on voltage-gated Ca2+ currents (ICa), and intracellular Ca2+ concentrations [( Ca2+]i) in cultured dorsal root ganglion (DRG) neurones of the rat were examined in vitro by use of combined patch clamp-microfluorometric recordings. 2. Under voltage-clamp conditions, capsaicin (0.1-10 microM) ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1990.tb12725.x
更新日期：1990-10-01 00:00:00
abstract：:1. Rabbit left atrial preparations driven electrically at different rates were used for studies on inotropic effects of cations, drugs and coupled pacing. Sino-atrial node-atrial preparations were used for investigating the chronotropic effect of noradrenaline.2. The contractile tension-driving rate relationship was m...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1969.tb09510.x
更新日期：1969-06-01 00:00:00
abstract：BACKGROUND AND PURPOSE:Sphingosine-1-phosphate (S1P) has been shown to be involved in the asthmatic disease as well in preclinical mouse experimental models of this disease. The aim of this study was to understand the mechanism(s) underlying S1P effects on the lung. EXPERIMENTAL APPROACH:BALB/c, mast cell-deficient an...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/bph.13033
更新日期：2015-04-01 00:00:00
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journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1983.tb10044.x
更新日期：1983-10-01 00:00:00
abstract：:In the rabbit isolated pulmonary artery, neither the ETA receptor antagonist, BQ-123 (10 microM), nor the ETB receptor antagonist, BQ-788 (10 microM), inhibited the contractions induced by 1 nM endothelin-1 (ET-1). However, the combination of BQ-123 and BQ-788 completely inhibited the ET-1-induced contraction. In cont...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1994.tb16901.x
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journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.2011.01602.x
更新日期：2012-02-01 00:00:00
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journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0704185
更新日期：2001-08-01 00:00:00
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journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1994.tb16204.x
更新日期：1994-09-01 00:00:00
abstract：:1 Poly (ADP-ribose) synthetase (PARS) is a nuclear enzyme activated by strand breaks in DNA, which are caused by reactive oxygen species (ROS). Here we investigate the effects of the PARS inhibitors 3-aminobenzamide (3-AB), nicotinamide and 1,5-dihydroxyisoquinoline (ISO) on the circulatory failure and the organ injur...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0702928
更新日期：1999-11-01 00:00:00
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journal_title：British journal of pharmacology
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doi：10.1111/j.1476-5381.1982.tb08776.x
更新日期：1982-01-01 00:00:00
abstract：:1. The role of sodium-calcium exchanger in acetylcholine (Ach)-induced hyperpolarization of intact endothelial cells was studied in excised rat aorta. The membrane potential was recorded using perforated patch-clamp technique. 2. The mean resting potential of endothelial cells was -44.1+/-1.4 mV. A selective inhibitor...
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pub_type： 杂志文章
doi：10.1038/sj.bjp.0705866
更新日期：2004-09-01 00:00:00
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更新日期：2000-02-01 00:00:00
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journal_title：British journal of pharmacology
pub_type： 杂志文章
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journal_title：British journal of pharmacology
pub_type： 杂志文章,评审
doi：10.1111/bph.15310
更新日期：2020-11-06 00:00:00
abstract：:1. In the present study the effect of N-methyl-D-aspartate (NMDA) on thromboxane B2 synthesis and on [Ca2+]i was studied in human platelets. 2. NMDA (10(-7) M) completely inhibited the synthesis of thromboxane B2 from exogenous arachidonic acid (AA), while it did not interfere with the aggregating effect of the thromb...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0701790
更新日期：1998-05-01 00:00:00
abstract：:The effects of treatment with rolipram, a specific phosphodiesterase IV inhibitor, on learning and memory function and on the cyclic AMP/PKA/CREB signal transduction system were examined in rats with microsphere embolism (ME)-induced cerebral ischaemia. Sustained cerebral ischaemia was induced by the injection of 900 ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0704629
更新日期：2002-04-01 00:00:00
abstract：:1. In order to assess the role of different ionic currents in hypoxia-induced action potential shortening, we investigated the effects of blockers of voltage-dependent and ATP-sensitive K(+)-channel on the membrane potential of hypoxic rabbit hearts and papillary muscles. The response to blocking of the inward rectifi...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1992.tb14436.x
更新日期：1992-08-01 00:00:00
