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[en] Drugs that block the cardiac K+ channel encoded by the human ether-à-go-go gene (hERG) have been associated with QT interval prolongation leading to proarrhythmia, and in some cases, sudden cardiac death. Because of special structural features of the hERG K+ channel, it has become a promiscuous target that interacts with pharmaceuticals of widely varying chemical structures and a reason for concern in the pharmaceutical industry. The structural diversity suggests that multiple binding sites are available on the channel with possible allosteric interactions between them. In the present study, three reference compounds and nine compounds of a previously disclosed series were evaluated for their allosteric effects on the binding of [3H]astemizole and [3H]dofetilide to the hERG K+ channel. LUF6200 was identified as an allosteric inhibitor in dissociation assays with both radioligands, yielding similar EC50 values in the low micromolar range. However, potassium ions increased the binding of the two radioligands in a concentration-dependent manner, and their EC50 values were not significantly different, indicating that potassium ions behaved as allosteric enhancers. Furthermore, addition of potassium ions resulted in a concentration-dependent leftward shift of the LUF6200 response curve, suggesting positive cooperativity and distinct allosteric sites for them. In conclusion, our investigations provide evidence for allosteric modulation of the hERG K+ channel, which is discussed in the light of findings on other ion channels. - Highlights: • Allosteric modulators on the hERG K+ channel were evaluated in binding assays. • LUF6200 was identified as a potent allosteric inhibitor. • Potassium ions were found to behave as allosteric enhancers. • Positive cooperativity and distinct allosteric sites for them were proposed
[en] Gonadotrophin-releasing hormone (GnRH) expression is associated with the two-pore domain potassium ion (K+) channel-related K+ (TREK) channel trek2a expression and melatonin levels. We aimed to investigate correlation of trek2a expression with gnrh3 expression, and regulatory mechanisms of trek2a expression by the melatonin receptor Mt1 and α2-adrenoceptor which are regulated by melatonin. trek2a specific siRNA, Mt1 antagonist luzindole and α2-adrenoceptor antagonist prazosin were administered into the adult zebrafish brain and gene expressions were examined by real-time PCR. trek2a specific siRNA administration significantly reduced expression levels of trek2a, gnrh3 and mt1. Luzindole administration suppressed trek2a and gnrh3 expressions. Prazosin administration reduced trek2a and gnrh3 expressions. It is suggested that Trek2a regulates gnrh3 expression under the control of Mt1 and α2-adrenoceptor.
[en] A green house study was conducted to see the role of two potassium sources i.e. SOP and MOP in improving salt-tolerance of four wheat varieties Viz Inqulah 91, Punjab 96, Bukhtawar and SARC II at three salinity levels of 0.9, 7.5 and 15 dS m-1 developed artificially. The data indicated that grain and straw yield, K contents in grain and straw and K/Na ratio in grain and straw decreased with increasing salinity levels while Na trend was reverse. Among the sources of K, SOP proved to the superior to MOP regarding grain and straw yield, K contents and K/Na ratio in grain and straw. Sodium contents were found maximum in MOP treated posts. The interactions among salinity levels, K sources and varieties were significant. Maximum grain and straw yield was noted at combination of EC, 0.9 dS m-1 x SOP in SARC II in case of grain and Bukhtawar in case of straw. At combinations of 7.5 dS m-1 X SOP and 15 dS m-1 x SOP, SARC II gave highest grain and straw yield. Potassium contents were found higher in SARC II at all combinations of salinity x SOP. Sodium contents were non-significant in case of grain and significant in case of straw but were least in Inqulab-91 (straw) at all combinations of salinity x MOP. The ratio of K Na in grain was found maximum in Punjab-96 at combination of EC, 0.9 dS m-1 x SOP while Inqulab-91 has highest K/Na ratios at other two combinations of salinity x SOP. In case of straw K/N was found highest in Inqulab-91 at all combinations of salinity x SOP. (author)
[en] A study was made of the effects of the herbicides 2,4-D and MCPA on the ion uptake, leakage and growth of rice seedlings. The isotopically-labelled solution contained different concentrations of 2,4-D (2,4-dichlorophenoxyacetic acid) or MCPA (4-chloro-2-methylphenoxyacetic acid). It was established that in the presence of 10-4M 2,4-D or MCPA the potassium ion uptake was effectively inhibited, while the K-ion leakage from the roots occurred only at 10-3M treatment. The growth of the rice seedlings was markedly retarded even at lower (10-6M) concentrations, and the roots and shoots tolerated the herbidie-treatment to different extents. At 10-8M herbicide concentration, the effects exhibited were not injurious, but rather favourable. Reduction in root length by herbicides was not in accordance with dry matter production. (author)
[en] The new thiophosphate salt K4In2(PS4)2(P2S6) (1), the selenophosphate salts K5In3(μ3-Se)(P2Se6)3 (2), K4In4(μ-Se)2(P2Se6)3 (3), and the mixed seleno-/thiophosphate salt K4In4(μ-Se)(P2S2.36Se3.64)3 (4) are described. For the first time, a structurally different outcome of a chalcophosphate reaction was observed when sulfur and selenium are mixed, for example, by the use of K2S/P2Se5/S/In instead of K2Se/P2Se5/Se/In or K2S/P2S5/S/In. In compounds 1-4 indium atoms exist in a variety coordination environments. While in 1, indium is octahedrally coordinated, in 2-4 tetrahedral, trigonal-bipyramidal, and octahedral coordination environments are found for indium atoms. This remarkable structural diversity possibly is a reason, why particularly indium chalcophosphate flux reactions often produce a large variety of compounds at intermediate temperatures. In the mixed seleno-/thiophosphate salt K4In4(μ-Se)(P2S2.36Se3.64)3 (4) most of the chalcogen sites around the tetrahedrally coordinated P atoms show mixed S/Se occupancy. There is, however, a preference for Se binding to In ions and S binding to potassium ions.
[en] Implantation of Walker 256 tumor decreases acute systemic inflammation in rats. Inflammatory hyperalgesia is one of the most important events of acute inflammation. The L-arginine/NO/cGMP/K"+ATP pathway has been proposed as the mechanism of peripheral antinociception mediated by several drugs and physical exercise. The objective of this study was to investigate a possible involvement of the NO/cGMP/K"+ATP pathway in antinociception induced in Walker 256 tumor-bearing male Wistar rats (180-220 g). The groups consisted of 5-6 animals. Mechanical inflammatory hypernociception was evaluated using an electronic version of the von Frey test. Walker tumor (4th and 7th day post-implantation) reduced prostaglandin E_2- (PGE_2, 400 ng/paw; 50 µL; intraplantar injection) and carrageenan-induced hypernociception (500 µg/paw; 100 µL; intraplantar injection). Walker tumor-induced analgesia was reversed (99.3% for carrageenan and 77.2% for PGE_2) by a selective inhibitor of nitric oxide synthase (L-NAME; 90 mg/kg, ip) and L-arginine (200 mg/kg, ip), which prevented (80% for carrageenan and 65% for PGE_2) the effect of L-NAME. Treatment with the soluble guanylyl cyclase inhibitor ODQ (100% for carrageenan and 95% for PGE_2; 8 µg/paw) and the ATP-sensitive K"+ channel (KATP) blocker glibenclamide (87.5% for carrageenan and 100% for PGE_2; 160 µg/paw) reversed the antinociceptive effect of tumor bearing in a statistically significant manner (P < 0.05). The present study confirmed an intrinsic peripheral antinociceptive effect of Walker tumor bearing in rats. This antinociceptive effect seemed to be mediated by activation of the NO/cGMP pathway followed by the opening of KATP channels
[en] In this work transition probabilities between Ievels of n < 11 for K and for the known of K+ are calculated. Two computer programs based on the Coulomb approximation and the most suitable coupling schemes has been used. Lifetimes of all these levels are also calculated. (Author)
[en] Highlights: • Decreased KCNQ1 expression was associated with a poor prognosis in HCC. • KCNQ1acts as a tumor suppressor in HCC. • KCNQ1 interacts with β-catenin to affect its subcellular distribution. • Activation of β-Catenin restores the inhibitory roles of KCNQ1 in HCC. Potassium (K+) channels are dysregulated in tumor tissues and functionally these channels contribute significantly to the malignant phenotypes of the cancer cells, including cell apoptosis, chemo- and radio-resistance, proliferation, and migration. However, little is known about the potential implications of K+ channels in hepatocellular carcinoma (HCC). The aim of the current study was to investigate the expression profile of KCNQ1 in HCC and assess its possible cellular implications as well as mechanism to disease progression. Using real-time qPCR and western blotting technique, we found that KCNQ1 was frequently down-regulated in HCC cell lines and tissues, and HCC patients with lower KCNQ1 expression had a poor prognosis. Specifically, DNA hypermethylation of KCNQ1 promoter resulted in its downregulation in HCC. Bioinformatic analysis indicated a regulatory role of KCNQ1 in the epithelial-to-mesenchymal transition process. Gain-of-function study showed that KCNQ1 exhibited remarkable inhibitory roles on tumor metastasis in vitro and in vivo. Mechanistically, KCNQ1 can interact with β-catenin to affect its subcellular distribution and subsequently reduce the activity of Wnt/β-catenin signaling, which further blocks the expression of its downstream targets, including c-Myc, MMP7, and CCND1. Restoration of β-catenin activity largely compromised the tumor-suppressive roles of KCNQ1 in the invasive capacity of HCC cells. In conclusion, KCNQ1 is down-regulated in HCC and may suppress HCC metastasis, which could represent a prognostic marker and promising therapeutic target for HCC.
[en] The data on chemical structures and specific activities of compounds functioning as histamine H_2-receptor antagonists, H+/K+-ATPase inhibitors at the exchange sites of hydrogen ions (proton pump inhibitors) and potassium ions (K+-competitive acid blockers) published from 1990 to 2013 are surveyed. The antisecretory agents with studied cytoprotective activity or with additional therapeutic properties compensating for disorders of internal defence mechanisms are presented. A separate section is devoted to the drugs that prevent or mitigate the NSAID-induced intestinal damage. All of the considered structures are classified according to the type of biological mechanism of action. Some aspects of the structure–activity relationships for such compounds are considered. The bibliography includes 83 references