Receptor-operated Channels Research Articles

Store-operated Ca2+ entry and depolarization explain the anomalous behaviour of myometrial SR: Effects of SERCA inhibition on electrical activity, Ca2+ and force

In the myometrium SR Ca2+ depletion promotes an increase in force but unlike several other smooth muscles, there is no Ca2+ sparks-STOCs coupling mechanism to explain this. Given the importance of the control of contractility for successful parturition, we have examined, in pregnant rat myometrium, the effects of SR Ca2+-ATPase (SERCA) inhibition on the temporal relationship between action potentials, Ca2+ transients and force. Simultaneous recording of electrical activity, calcium and force showed that SERCA inhibition, by cyclopiazonic acid (CPA 20μM), caused time-dependent changes in excitability, most noticeably depolarization and elevations of baseline [Ca2+]i and force. At the onset of these changes there was a prolongation of the bursts of action potentials and a corresponding series of Ca2+ spikes, which increased the amplitude and duration of contractions. As the rise of baseline Ca2+ and depolarization continued a point was reached when electrical and Ca2+ spikes and phasic contractions ceased, and a maintained, tonic force and Ca2+ was produced. Lanthanum, a non-selective blocker of store-operated Ca2+ entry, but not the L-type Ca2+ channel blocker nifedipine (1–10μM), could abolish the maintained force and calcium. Application of the agonist, carbachol, produced similar effects to CPA, i.e. depolarization, elevation of force and calcium. A brief, high concentration of carbachol, to cause SR Ca2+ depletion without eliciting receptor-operated channel opening, also produced these results. The data obtained suggest that in pregnant rats SR Ca2+ release is coupled to marked Ca2+ entry, via store operated Ca2+ channels, leading to depolarization and enhanced electrical and mechanical activity.

Novel phthalamides containing sulfiliminyl moieties and derivatives as potential ryanodine receptor modulators.

To tackle the serious challenge of insect resistance and stricter environmental regulations, innovating a new eco-friendly insecticide is urgently required. A series of new phthalamides containing sulfiliminyl and sulfoximinyl moieties were designed and synthesized. In total, 30 new structures were characterized by 1H NMR spectra and HRMS. The bioassay results indicated that some title compounds exhibited excellent insecticidal activities against oriental armyworm (Pseudaletia separata Walker) and diamondback moth (Plutella xylostella (L.)). 4a showed the same larvicidal level as that of commercial flubendiamide as a control. 7a and 9a exhibited outstanding activity against diamondback moth. The LC50 values of 7a and 9a were 8.33 × 10(−8) and 2.34 × 10(−8) mg L(−1), respectively, lower than that of flubendiamide (1.25 × 10(−7) mg L(−1)). The effects of 4a, 7a and 9a on intracellular calcium of neurons from the beet armyworm (Spodoptera exigua) indicated that these title compounds activate the receptor-operated calcium channel. The calcium ions efflux from the calcium store on endoplasmic reticulum (ER) when treated with novel compounds. The results of CoMFA calculation showed that N-cyanosulfilimines and N-trifluoroacetylsulfoximines might be of importance to the larvicidal activity. The present work demonstrated that structures containing sulfiliminyl and sulfoximinyl moieties can be considered as lead compounds for the development of new insect ryanodine receptor modulators.

Why isn't endogenous ouabain more widely accepted?

A new idea is the most quickly acting antigen known to science . —Wilfred Trotter During the past few years, several distinguished senior colleagues who visited our department and inquired about the status of endogenous ouabain (EO) have asked, “How come I didn't know about these [published]

Arachidonate-Regulated Ca2+ Influx in Human Airway Smooth Muscle

Plasma membrane Ca(2+) influx, especially store-operated Ca(2+) entry triggered by sarcoplasmic reticulum (SR) Ca(2+) release, is a key component of intracellular calcium concentration ([Ca(2+)]i) regulation in airway smooth muscle (ASM). Agonist-induced Ca(2+) oscillations in ASM that involve both influx and SR mechanisms have been previously demonstrated. In nonexcitable cells, [Ca(2+)]i oscillations involve Ca(2+) influx via arachidonic acid (AA) -stimulated channels, which show similarities to store-operated Ca(2+) entry, although their molecular identity remains undetermined. Little is known about AA-regulated Ca(2+) channels or their regulation in ASM. In enzymatically dissociated human ASM cells loaded with the Ca(2+) indicator, fura-2, AA (1-10 μM) triggered [Ca(2+)]i oscillations that were inhibited by removal of extracellular Ca(2+). Other fatty acids, such as the diacylglycerol analog, 1-oleoyl-2-acetyl-SN-glycerol, oleic acid, and palmitic acid (10 μM each), failed to elicit similar [Ca(2+)]i responses. Preincubation with LaCl3 (1 μM or 1 mM) inhibited AA-induced oscillations. Inhibition of receptor-operated channels (SKF96,365 [10 μM]), lipoxygenase (zileuton [10 μM]), or cyclooxygenase (indomethacin [10 μM]) did not affect oscillation parameters. Inhibition of SR Ca(2+) release (ryanodine [10 μM] or inositol 1,4,5-trisphosphate receptor inhibitor, xestospongin C [1 μM]) decreased [Ca(2+)]i oscillation frequency and amplitude. Small interfering RNA against caveolin-1, stromal interaction molecule 1, or Orai3 (20 nM each) reduced the frequency and amplitude of AA-induced [Ca(2+)]i oscillations. In ASM cells derived from individuals with asthma, AA increased oscillation amplitude, but not frequency. These results are highly suggestive of a novel AA-mediated Ca(2+)-regulatory mechanism in human ASM, reminiscent of agonist-induced oscillations. Given the role of AA in ASM intracellular signaling, especially with inflammation, AA-regulated Ca(2+) channels could potentially contribute to increased [Ca(2+)]i in diseases such asthma.

Calcium sensing receptor modulates extracellular calcium entry and proliferation via TRPC3/6 channels in cultured human mesangial cells.

Calcium-sensing receptor (CaSR) has been demonstrated to be present in several tissues and cells unrelated to systemic calcium homeostasis, where it regulates a series of diverse cellular functions. A previous study indicated that CaSR is expressed in mouse glomerular mesangial cells (MCs), and stimulation of CaSR induces cell proliferation. However, the signaling cascades initiated by CaSR activation in MCs are currently unknown. In this study, our data demonstrate that CaSR mRNA and protein are expressed in a human mesangial cell line. Activating CaSR with high extracellular Ca2+ concentration ([Ca2+]o) or spermine induces a phospholipase C (PLC)-dependent increase in intracellular Ca2+ concentration ([Ca2+]i). Interestingly, the CaSR activation-induced increase in [Ca2+]i results not only from intracellular Ca2+ release from internal stores but also from canonical transient receptor potential (TRPC)-dependent Ca2+ influx. This increase in Ca2+ was attenuated by treatment with a nonselective TRPC channel blocker but not by treatment with a voltage-gated calcium blocker or Na+/Ca2+ exchanger inhibitor. Furthermore, stimulation of CaSR by high [Ca2+]o enhanced the expression of TRPC3 and TRPC6 but not TRPC1 and TRPC4, and siRNA targeting TRPC3 and TRPC6 attenuated the CaSR activation-induced [Ca2+]i increase. Further experiments indicate that 1-oleoyl-2-acetyl-sn-glycerol (OAG), a known activator of receptor-operated calcium channels, significantly enhances the CaSR activation-induced [Ca2+]i increase. Moreover, under conditions in which intracellular stores were already depleted with thapsigargin (TG), CaSR agonists also induced an increase in [Ca2+]i, suggesting that calcium influx stimulated by CaSR agonists does not require the release of calcium stores. Finally, our data indicate that pharmacological inhibition and knock down of TRPC3 and TRPC6 attenuates the CaSR activation-induced cell proliferation in human MCs. With these data, we conclude that CaSR activation mediates Ca2+ influx and cell proliferation via TRPC3 and TRPC6 in human MCs.

Mechanism of inhibition of the GluA1 AMPA receptor channel opening by the 2,3-benzodiazepine compound GYKI 52466 and a N-methyl-carbamoyl derivative.

2,3-Benzodiazepine derivatives, also known as GYKI compounds, represent a group of the most promising synthetic inhibitors of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Here we investigate the mechanism of inhibition of the GluA1 channel opening and the site of inhibition by GYKI 52466 and its N-3 methyl-carbamoyl derivative, which we term as BDZ-f. GluA1 is a key AMPA receptor subunit involved in the brain function. Excessive activity and elevated expression of GluA1, however, has been implicated in a number of neurological disorders. Using a laser-pulse photolysis technique, which provides ∼60 μs resolution, we measured the effect of these inhibitors on the rate of GluA1 channel opening and the amplitude of the glutamate-induced whole-cell current. We found that both compounds inhibit GluA1 channel noncompetitively. Addition of an N-3 methyl-carbamoyl group to the diazepine ring with the azomethine feature (i.e., GYKI 52466) improves the potency of the resulting compound or BDZ-f without changing the site of binding. This site, which we previously termed as the “M” site on the GluA2 AMPA receptor subunit, therefore favorably accommodates an N-3 acylating group. On the basis of the magnitude of the inhibition constants for the same inhibitors but different receptors, the “M” sites on GluA1 and GuA2 are different. Overall, the “M” site or the binding environment on GluA2 accommodates the same compounds better, or the same inhibitors show stronger potency on GluA2, as we have reported previously [Wang et al. Biochemistry (2011) 50, 7284−729321751782]. However, acylating the N-3 position to occupy the N-3 side pocket of the “M” site can significantly narrow the difference and improve the potency of a resulting compound on GluA1.

Studies on the resolution of subcellular free calcium concentrations: a technological advance. Focus on “Detection of differentially regulated subsarcolemmal calcium signals activated by vasoactive agonists in rat pulmonary artery smooth muscle cells”

One of the most striking facts about the elements is their unequal distribution and occurrence in nature . —C. R. Hammond free calcium is highly controlled in biological tissues, and much like the physical chemistry of elements ([5][1]), its concentration is unequal in distribution (for recent

The relaxant effect of propofol on isolated rat intrapulmonary arteries.

Propofol is a widely used anesthetic. Many studies have shown that propofol has direct effects on blood vessels, but the precise mechanism is not fully understood. Secondary intrapulmonary artery rings from male rats were prepared and mounted in a Multi Myograph System. The following constrictors were used to induce contractions in isolated artery rings: high K+ solution (60 mmol/L); U46619 solution (100 nmol/L); 5-hydroxytryptamine (5-HT; 3 µmol/L); or phenylephrine (Phe; 1 µmol/L). The relaxation effects of propofol were tested on high K+ or U46619 precontracted rings. Propofol also was added to induce relaxation of rings preconstricted by U46619 after pretreatment with the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). The effects of propofol on Ca2+ influx via the L-type Ca2+ channels were evaluated by examining contraction-dependent responses to CaCl2 in the absence or presence of propofol (10 to 300 µmol/L). High K+ solution and U46619 induced remarkable contractions of the rings, whereas contractions induced by 5-HT and Phe were weak. Propofol induced dose-dependent relaxation of artery rings precontracted by the high K+ solution. Propofol also induced relaxation of rings precontracted by U46619 in an endothelium-independent way. Propofol at different concentrations significantly inhibited the Ca2+-induced contractions of pulmonary rings exposed to high K+-containing and Ca2+-free solution in a dose-dependent manner. Propofol relaxed vessels precontracted by the high K+ solution and U46619 in an endothelium-independent way. The mechanism for this effect may involve inhibition of calcium influx through voltage-operated calcium channels (VOCCs) and receptor-operated calcium channels (ROCCs).

Patch clamp combined with voltage/concentration clamp to determine the kinetics and voltage dependency of N-methyl-D-aspartate (NMDA) receptor open channel blockers.

Electrophysiological techniques can be used to great effect to help determine the mechanism of action of a compound. However, many factors can compromise the resulting data and their analysis, such as the speed of solution exchange, expression of additional ion channel populations including other ligand-gated receptors and voltage-gated channels, compounds having multiple binding sites, and current desensitization and rundown. In this chapter, such problems and their solutions are discussed and illustrated using data from experiments involving the uncompetitive NMDA receptor antagonist memantine. Memantine differs from many other NMDA receptor channel blockers in that it is well tolerated and does not cause psychotomimetic effects at therapeutic doses. Various electrophysiological parameters of NMDA-induced current blockade by memantine have been proposed to be important in determining therapeutic tolerability; potency, onset and offset kinetics, and voltage dependency. These were all measured using whole cell patch clamp techniques using hippocampal neurons. Full results are shown here for memantine, and these are summarized and compared to those from similar experiments with other NMDA channel blockers. The interpretation of these results is discussed, as are theories concerning the tolerability of NMDA channel blockers, with the aim of illustrating how electrophysiological data can be used to form and support a physiological hypothesis.

Negative regulation of endothelin type A receptor-operated TRPC6 channel by adenylate cyclase-camp-protein kinase a signaling pathway

Negative regulation of endothelin type A receptor-operated TRPC6 channel by adenylate cyclase-camp-protein kinase a signaling pathway

Endothelin‐1 and endothelin‐2 initiate and maintain contractile responses by different mechanisms in rat mesenteric and cerebral arteries

Endothelin (ET)-1 and ET-2 cause potent long-lasting vasoconstrictions by tight binding to smooth muscle ETA receptors. We tested the hypotheses that different mechanisms mediate initiation and maintenance of arterial contractile responses to ET-1 and ET-2 and that this differs among vascular beds. Segments of rat mesenteric resistance artery (MRA) and basilar artery (BA) were studied in wire myographs with and without functional antagonists. Sensitivity and maximum of MRA contractile responses to ET-1 were not, or only moderately, reduced by stimulation of soluble GC, AC or K(+) -channels and by an inhibitor of receptor-operated ion channels. However, each of these reduced maintenance of ET-1 effects and relaxed ET-1-induced contractions in MRA. A calcium channel antagonist did not alter sensitivity, maximum and maintenance of ET-1 effects, but relaxed ET-1-induced contractions in MRA. A PLC inhibitor prevented contractile responses to ET-1 and ET-2 in MRA and BA, and relaxed ET-1- and ET-2-induced responses in MRA and ET-1 effects in BA. A Rho-kinase inhibitor did not modify sensitivity, maximum and maintenance of responses to both peptides in both arteries but relaxed ET-2, but not ET-1, effects in MRA and ET-1 effects in BA. PLC played a key role in arterial contractile responses to ETs, but ET-1 and ET-2 initiated and maintained vasoconstriction through different mechanisms, and these differed between MRA and BA. Selective functional antagonism may be considered for agonist- and vascular bed selective pharmacotherapy of ET-related diseases.

Inter- and intrasubunit interactions between transmembrane helices in the open state of P2X receptor channels

P2X receptor channels open in response to the binding of extracellular ATP, a property that is essential for purinergic sensory signaling. Apo and ATP-bound X-ray structures of the detergent-solubilized zebrafish P2X4 receptor provide a blueprint for receptor mechanisms but unexpectedly showed large crevices between subunits within the transmembrane (TM) domain of the ATP-bound structure. Here we investigate both intersubunit and intrasubunit interactions between TM helices of P2X receptors in membranes using both computational and functional approaches. Our results suggest that intersubunit crevices found in the TM domain of the ATP-bound crystal structure are not present in membrane-embedded receptors but substantiate helix interactions within individual subunits and identify a hot spot at the internal end of the pore where both the gating and permeation properties of P2X receptors can be tuned. We propose a model for the structure of the open state that has stabilizing intersubunit interactions and that is compatible with available structural constraints from functional channels in membrane environments.

Serotonin receptors take the TRiPV4 highway in chronic hypoxic pulmonary hypertension. Focus on “TRPV4 channel contributes to serotonin-induced pulmonary vasoconstriction and the enhanced vascular reactivity in chronic hypoxic pulmonary hypertension”

pulmonary arterial hypertension (PAH) is a rare human disease displaying a very poor prognosis of survival. The chronic increase in pulmonary vascular resistance associated with PAH eventually leads to right ventricular hypertrophy and failure, and ultimately death. It is well accepted that the

Vasorelaxant and antihypertensive effects of methanolic fraction of the essential oil of Alpinia zerumbet

Alpinia zerumbet is used in folk medicine in Brazil to treat hypertension. However, several pathways involved in the mechanism of vasorelaxation are still unclear. This study was designed to verify the antihypertensive effect of the methanolic fraction of the essential oil of A. zerumbet (MFEOAz) and to characterize its mechanism of action. The thoracic aortic rings from the Wistar rats were perfused in the organ chambers filled with Kreb's solution, where the tension of each ring was measured. The antihypertensive effect of MFEOAz was assessed in rats submitted to chronic hypertension by inhibition of nitric oxide synthesis by indirect measurement of blood pressure with indirect tail cuff method. MFEOAz relaxed phenylephrine and KCl-induced contraction of either endothelium-intact or endothelium-denuded rat aortic rings in a concentration-dependent manner. Pre-incubation with MFEOAz (100 and 300μg/mL) in Ca2+-free Krebs solution attenuated phenylephrine- or caffeine-induced contraction. Pre-incubation with L-NAME, ODQ, wortmannin, atropine, indomethacin, catalase, SOD, TEA, 4-aminopyridine, glibenclamide, apamin, charybdotoxin, or iberiotoxin did not affect MFEOAz-induced relaxation. The intragastric administration of MFEOAz induced an antihypertensive effect. MFEOAz it seems inhibited the calcium influx via voltage-operated calcium channels and receptor-operated calcium channels, as well as inhibition of calcium mobilization from intracellular stores.

Histidine triad nucleotide-binding protein 1 (HINT1) regulates Ca2+ signaling in mouse fibroblasts and neuronal cells via store-operated Ca2+ entry pathway

Recent findings indicate that histidine triad nucleotide-binding protein 1 (HINT1) is implicated in the pathophysiology of certain psychiatric disorders and also exhibits tumor suppressor properties. However, the authentic functions of HINT1 in cellular physiology and especially its role in Ca(2+) signaling remain unclear. Here, we studied Ca(2+) signaling in cultured embryonic fibroblasts derived from wild-type control and HINT1 knockout (KO) mice. The resting cytosolic Ca(2+) level (measured with fura-2) was not altered in fibroblasts lacking HINT1. The stored Ca(2+) evaluated by measuring peak amplitude of ATP (10 μM)-induced Ca(2+) transients in Ca(2+)-free medium was significantly larger in HINT1 KO fibroblasts than in wild-type cells. Ca(2+) influx after external Ca(2+) restoration, likely via store- and receptor-operated channels (SOCs and ROCs, respectively), was greatly (by 2-fold) reduced in HINT1 KO fibroblasts. This correlated with a downregulated expression of Orai1 and stromal interacting molecule 1 (STIM1), essential components of store-operated Ca(2+) entry pathway. Expression of canonical transient receptor potential (TRPC)3 and TRPC6, which function as ROCs, was not altered in HINT1 KO fibroblasts. Immunoblots also revealed that Orai1 was downregulated by twofold in brain lysates of HINT1 KO mice compared with the wild-type littermates. Importantly, silencer RNA knockdown of HINT1 in Neuro-2A cells markedly downregulated Orai1 and STIM1 protein expression and significantly (by 2.5-fold) reduced ATP-induced Ca(2+) influx, while ATP-evoked Ca(2+) release was not changed. Thus the study demonstrates a novel function of HINT1 that involves the regulation of SOC-mediated Ca(2+) entry pathway (Orai1 and STIM1), essential for regulation of cellular Ca(2+) homeostasis.

Potential contribution of SOCC to cerebral vasospasm after experimental subarachnoid hemorrhage in rats

Cerebral vasospasm (CVS) is the most treatable component of subarachnoid hemorrhage (SAH), which can be reduced by endothelin receptor antagonists. Endothelin-evoked vasospasm is considered to be mediated by Ca2+ influx in the smooth muscle through voltage-dependent Ca2+ channel (VDCC) and nonselective cation channels (NSCC). Because VDCC antagonists such as nimodipine have been shown to be relatively less effective than the endothelin receptor antagonists, it is assumed that NSCC maybe a more important component in mediating Ca2+ influx during CVS. In this study, we used the basilar arteries from a “two-hemorrhage” rat model of SAH to investigate expressions of transient receptor potential channel 1 (TRPC1), transient receptor potential channel 3 (TRPC3) and stromal interaction molecule 1 (STIM1), which are considered as the promising candidates constituting NSCC. To investigate the possible role of NSCC in phenotypic switching, we performed immunohistochemical staining to examine expressions of SMα-actin and PCNA, markers of smooth muscle phenotypic switching. We found that the basilar arteries exhibited vasospasm after SAH and that vasospasm became more severe on days 5 and 7 after SAH. Elevated mRNA and protein expressions of TRPC1 and STIM1 were detected after SAH and peaked on days 5 and 7, which was in a parallel time course to the development of cerebral vasospasm. The mRNA and protein expressions of TRPC3 were not changed in the SAH group when compared with those in the control. Results of immunohistochemical staining with anti-PCNA and anti-SMα-actin antibodies also showed enhanced expression of PCNA and disappearance of SMα-actin from day 1 to day 7. Taken together, the above results supported a novel mechanism that the components of store-operated calcium channels, TRPC1 and STIM1 mediated the Ca2+ influx and phenotypic switching in smooth muscle cells, which promoted the development of vasospasm after SAH. TRPC3, which is a component of receptor-operated calcium channels, was not involved in the above-mentioned mechanism.

Mechanism of Inhibition of the GluA2 AMPA Receptor Channel Opening by Talampanel and Its Enantiomer: The Stereochemistry of the 4-Methyl Group on the Diazepine Ring of 2,3-Benzodiazepine Derivatives

Stereoselectivity of 2,3-benzodiazepine compounds provides a unique way for the design of stereoisomers as more selective and more potent inhibitors as drug candidates for treatment of the neurological diseases involving excessive activity of AMPA receptors. Here we investigate a pair of enantiomers known as Talampanel and its (+) counterpart about their mechanism of inhibition and selectivity toward four AMPA receptor subunits or GluA1-4. We show that Talampanel is the eutomer with the endismic ratio being 14 for the closed-channel and 10 for the open-channel state of GluA2. Kinetic evidence supports that Talampanel is a noncompetitive inhibitor and it binds to the same site for those 2,3-benzodiazepine compounds with the C-4 methyl group on the diazepine ring. This site, which we term as the "M" site, recognizes preferentially those 2,3-benzodiazepine compounds with the C-4 methyl group being in the R configuration, as in the chemical structure of Talampanel. Given that Talampanel inhibits GluA1 and GluA2, but is virtually ineffective on the GluA3 and GluA4 AMPA receptor subunits, we hypothesize that the "M" site(s) on GluA1 and GluA2 to which Talampanel binds is different from that on GluA3 and GluA4. If the molecular properties of the AMPA receptors and Talampanel are used for selecting an inhibitor as a single drug candidate for controlling the activity of all AMPA receptors in vivo, Talampanel is not ideal. Our results further suggest that addition of longer acyl groups to the N-3 position should produce more potent 2,3-benzodiazepine inhibitors for the "M" site.

Recovery of NMDA receptor currents from MK-801 blockade is accelerated by Mg2+ and memantine under conditions of agonist exposure

MK-801 is a use-dependent NMDA receptor open channel blocker with a very slow off-rate. These properties can be exploited to ‘pre-block’ a population of NMDARs, such as synaptic ones, enabling the selective activation of a different population, such as extrasynaptic NMDARs. However, the usefulness of this approach is dependent on the stability of MK-801 blockade after washout. We have revisited this issue, and confirm that recovery of NMDAR currents from MK-801 blockade is enhanced by channel opening by NMDA, and find that it is further increased when Mg2+ is also present. In the presence of Mg2+, 50% recovery from MK-801 blockade is achieved after 10′ of 100 μM NMDA, or 30′ of 15 μM NMDA exposure. In Mg2+-free medium, NMDA-induced MK-801 dissociation was found to be much slower. Memantine, another PCP-site antagonist, could substitute for Mg2+ in accelerating the unblock of MK-801 in the presence of NMDA. This suggests a model whereby, upon dissociation from its binding site in the pore, MK-801 is able to re-bind in a process antagonized by Mg2+ or another PCP-site antagonist. Finally we show that even when all NMDARs are pre-blocked by MK-801, incubation of neurons with 100 μM NMDA in the presence of Mg2+ for 2.5 h triggers sufficient unblocking to kill >80% of neurons. We conclude that while synaptic MK-801 ‘pre-block’ protocols are useful for pharmacologically assessing synaptic vs. extrasynaptic contributions to NMDAR currents, or studying short-term effects, it is problematic to use this technique to attempt to study the effects of long-term selective extrasynaptic NMDAR activation.This article is part of the Special Issue entitled ‘Glutamate Receptor-Dependent Synaptic Plasticity’.

Mechanism of Inhibition of the GluA2 AMPA Receptor Channel Opening by 2,3-Benzodiazepine Derivatives

Mechanism of Inhibition of the GluA2 AMPA Receptor Channel Opening by 2,3-Benzodiazepine Derivatives

An open-label trial of memantine in treatment-resistant obsessive-compulsive disorder.

Background:Obsessive-compulsive disorder (OCD) is often refractory to treatment. Glutamatergic neurotransmission modulating agents like memantine, an N-methyl-D-aspartate receptor open channel blocker (antagonist), has been reported to be beneficial in OCD.Materials and Methods:Twelve subjects of OCD who had been on various medications for over 5 years, but were poor responders, were enrolled for a 12-week open-label trial with fixed dose trial of memantine as an augmenting agent. The OCD symptoms and adverse effects of the drug were monitored.Results:Out of 12 subjects, eight had clear benefit, with reduction of 25% or more on Yale-Brown Obsessive-Compulsive Scale, and there were no side-effects with the medication,Conclusion:Memantine may be beneficial for treatment-resistant OCD as an augmenting agent.