The human ether-a-go-go related gene （hERG） channel is responsible for the repolarization during the action potential, and blockage of that may result in severe cardiotoxicity and sudden death. In this study, a data...The human ether-a-go-go related gene （hERG） channel is responsible for the repolarization during the action potential, and blockage of that may result in severe cardiotoxicity and sudden death. In this study, a dataset containing 1969 compounds was compiled from literature and FDA-approved drugs. Using a support vector machine （SVM）, two groups of computational models were built to distinguish whether a compound is a blocker or non-blocker of hERG potassium ion channel. These mod- els fit generally satisfactory. The 100 models built with MACCS fingerprints （Model Group A） showed an average accuracy of 90% and an average matthews correlation coefficient （MCC） value of 0.77 on the test sets. The 100 models built with selected MOE descriptors （Model Group B） showed an average accuracy of 89% and an average MCC value of 0.74 on the test sets. Molecular hydrophobicity and lipophilicity were found to be very important factors which lead to block the hERG potassium ion channel. Some other molecular properties such as electrostatic properties, features based on van der Waals surface area, the number of rigid bonds and molecular surface rugosity also played important roles in blocking bERG potassium ion channel.展开更多
The purpose of this study is to investigate the expression of major potassium channel subtypes in the brain of chronical mild stress (CMS) rats and reveal the effects of fluoxetine on the expression of these channels....The purpose of this study is to investigate the expression of major potassium channel subtypes in the brain of chronical mild stress (CMS) rats and reveal the effects of fluoxetine on the expression of these channels. Rats were exposed to a variety of unpredictable stress for three weeks and induced anhedonia, lower sucrose preference, locomotor activity and lower body weight The protein expressions were determined by Western blot. CMS significantly increased the expression of Kv2.1 channel in frontal cortex but not in hippocampus, and the expression level was normalized after fluoxetine treatment. the expression of TREK-1 channel was also obviously increased in frontal cortex in CMS rats. Fluoxetine treatment might prevent this increase. However, the expression of Kv3.1 and Kv4.2 channels was considerably decreased in hippocampus after CMS, and was not affected by fluoxetine. These results suggest that different subtypes of potassium channels are associated with the pathophy-siology of depression and that the therapeutical effects of fluoxetine may relate to Kv2.1 and TREK-1 potassium channels. (C) 2015 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. All rights reserved.展开更多
Although it has been more than 165 years since the first introduction of modern anesthesia to the clinic, there is surprisingly little understanding about the exact mechanisms by which general anesthetics induce uncon...Although it has been more than 165 years since the first introduction of modern anesthesia to the clinic, there is surprisingly little understanding about the exact mechanisms by which general anesthetics induce unconsciousness. As a result, we do not know how general anesthetics produce anesthesia at different levels. The main handicap to understanding the mechanisms of general anesthesia is the diversity of chemically unrelated compounds including diethyl ether and halogenated hydrocarbons, gases nitrous oxide, ketamine, propofol, benzodiazepines and etomidate, as well as alcohols and barbiturates. Does this imply that general anesthesia is caused by many different mechanisms? Until now, many receptors, molecular targets and neuronal transmission pathways have been shown to contribute to mechanisms of general anesthesia. Among these molecular targets, ion channels are the most likely candidates for general anesthesia, in particular γ-aminobutyric acid type A, potassium and sodium channels, as well as ion channels mediated by various neuronal transmitters like acetylcholine, amino acids amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid or N-methyl-D-aspartate. In addition, recent studies have demonstrated the involvement in general anesthesia of other ion channels with distinct gating properties suchas hyperpolarization-activated, cyclic- nucleotide-gated channels. The main aim of the present review is to summarize some aspects of current knowledge of the effects of general anesthetics on various ion channels.展开更多
To study the gating kinetics of voltage dependent K + channel in clonal pheochromocytoma (PC12) cells, the inward currents of K channel in PC12 cells were recorded using cell attached patch clamp technique. The fracta...To study the gating kinetics of voltage dependent K + channel in clonal pheochromocytoma (PC12) cells, the inward currents of K channel in PC12 cells were recorded using cell attached patch clamp technique. The fractal features of the open and closed time distributions were determined. The fractal dimensions and kinetic setpoints for the open and closed durations were estimated. It was found that the fractal dimension D was independent of voltage and the logarithm logA of the setpoint A was inversely proportional to the pipette potential (Vp) for the closed durations. While for the open durations the fractal dimension D was inversely proportional to the pipette potential and the logarithm logA of the setpoint A was independent of voltage. Thus, for this channel the open and closed durations and voltage dependence of the gating could be well described by the fractal model.展开更多
Objective The expression of HERG in common bone tumors is scarcely reported and there is a lack of dedicated studies.This study aimed to investigated the expression of HERG in several common musculoskeletal tumors.Met...Objective The expression of HERG in common bone tumors is scarcely reported and there is a lack of dedicated studies.This study aimed to investigated the expression of HERG in several common musculoskeletal tumors.Methods Immunohistochemical staining,RT-PCR,and Western blotting were used to observe HERG expression differences in various tissues and cell lines.Results HERG was differentially expressed in different malignant tumors,both at a differential protein level and localization within tumors.HERG was not expressed in normal bone tissue.The HERG inhibitor E-4031 markedly inhibited the proliferation of osteosarcoma cell lines.Conclusion HERG was highly expressed in malignant tumors.Blocking of HERG can effectively inhibit the proliferation of bone tumors.展开更多
Objective： Our group has previously observed that in patients with small-cell lung cancers （SCLCs）, the expression of a tumor antigen, glioma big potassium （gBK） ion channel, is higher at the time of death than w...Objective： Our group has previously observed that in patients with small-cell lung cancers （SCLCs）, the expression of a tumor antigen, glioma big potassium （gBK） ion channel, is higher at the time of death than when the cancer is first treated by surgical resection. This study aimed to determine whether this dichotomy was common in other potential lung tumor antigens by examining the same patient samples using our more extensive profile analysis of tumor-antigen precursor protein （TAPP）. We then tested the hypothesis that therapeutic intervention may inadvertently cause this increased gBK production. Methods： SCLC samples （eight surgical resections and three autopsy samples） and three control lungs were examined by quantitative real-time polymerase chain reaction for 42 potential TAPPs that represent potential T-cell-mediated immunological targets. Results： Twenty-two TAPP mRNAs displayed the same profile as gBK, i.e., more mRNAs were expressed at autopsy than in their surgical counterparts. B-cyclin and mouse double minute 2, human homolog of PS3-binding protein were elevated in both autopsy and surgical specimens above the normal-lung controls. When HTB119 cells were incubated with doxorubicin, gBK was strongly induced, as confirmed by intracellular flow cytometry with a gBK-specific antibody. Conclusion： Our findings suggested that more immunological targets became available as the tumor responded to chemotherapy and proceeded toward its terminal stages.展开更多
Thalamic hemorrhage can lead to the development of central post-stroke pain.Changes in histone acetylation levels,which are regulated by histone deacetylases,affect the excitability of neurons surrounding the hemorrha...Thalamic hemorrhage can lead to the development of central post-stroke pain.Changes in histone acetylation levels,which are regulated by histone deacetylases,affect the excitability of neurons surrounding the hemorrhagic area.However,the regulato ry mechanism of histone deacetylases in central post-stroke pain remains unclea r.Here,we show that iron overload leads to an increase in histone deacetylase 2expression in damaged ventral posterolateral nucleus neurons.Inhibiting this increase restored histone H3 acetylation in the Kcna2 promoter region of the voltage-dependent potassium(Kv)channel subunit gene in a rat model of central post-stroke pain,thereby increasing Kcna2expression and relieving central pain.However,in the absence of nerve injury,increasing histone deacetylase 2 expression decreased Kcna2expression,decreased Kv current,increased the excitability of neurons in the ventral posterolateral nucleus area,and led to neuropathic pain symptoms.Moreover,treatment with the iron chelator deferiprone effectively reduced iron overload in the ventral posterolateral nucleus after intracerebral hemorrhage,reversed histone deacetylase 2 upregulation and Kv1.2 downregulation,and alleviated mechanical hypersensitivity in central post-stroke pain rats.These results suggest that histone deacetylase 2 upregulation and Kv1.2 downregulation,mediated by iron overload,are important factors in central post-stroke pain pathogenesis and co uld se rve as new to rgets for central poststroke pain treatment.展开更多
A three-state hopping model is established ac-cording to experiments to study permeation of an open-state potassium channel from Streptomyces Lividans (KcsA po-tassium channel). The master equations are used to charac...A three-state hopping model is established ac-cording to experiments to study permeation of an open-state potassium channel from Streptomyces Lividans (KcsA po-tassium channel). The master equations are used to charac-terize the dynamics of the system. In this model, ion conduc-tion involves transitions of three states, with one three-ion state and two two-ion states in the selectivity filter respec-tively. In equilibrium, the well-known Nernst equation is deduced. It is further shown that the current follows Micha-elis-Menten kinetics in steady state. According to the pa-rameters provided by Nelson, the current-voltage relation-ship is proved to be ohmic and the current-concentration relationship is also obtained reasonably. Additional valida-tion of the model in the characteristic time to reach the steady state for the potassium channel is also discussed. This model lays a possible physical basis for the permeation of ion channel, and opens an avenue for further research.展开更多
Background Ketanserin （KT）, a selective serotonin （5-HT） 2-receptor antagonist, reduces peripheral blood pressure by blocking the activation of peripheral 5-HT receptors. In this study electrophysiological method ...Background Ketanserin （KT）, a selective serotonin （5-HT） 2-receptor antagonist, reduces peripheral blood pressure by blocking the activation of peripheral 5-HT receptors. In this study electrophysiological method was used to investigate the effect of KT and potassium ion on Kv1.3 potassium channels and explore the role of blocker KT in the alteration of channel kinetics contributing to the potassium ion imbalances. Methods Kv1.3 channels were expressed in xenopus oocytes, and currents were measured using the two-microelectrode voltage-clamp technique. Results KCI made a left shift of activation and an inactivation curve of Kv1.3 current and accelerated the activation and inactivation time constant. High extracellular [K^＋] attenuated the blockade effect of KT on Kv1.3 channels. In the presence of KT and KCI the activation and inactivation time constants were not influenced significantly no matter what was administered first. KT did not significantly inhibit Kv1.3 current induced by tetraethylammonium （TEA）. Conclusions KT is a weak blocker of Kv1.3 channels at different concentrations of extracellular potassium and binds to the intracellular side of the channel pore. The inhibitor KT of ion channels is not fully effective in clinical use because of high [K^＋]. and other electrolyte disorders.展开更多
基金supported by the National Natural Science Foundation of China(20975011)"Chemical Grid Project"of Beijing University of Chemical Technology
文摘The human ether-a-go-go related gene （hERG） channel is responsible for the repolarization during the action potential, and blockage of that may result in severe cardiotoxicity and sudden death. In this study, a dataset containing 1969 compounds was compiled from literature and FDA-approved drugs. Using a support vector machine （SVM）, two groups of computational models were built to distinguish whether a compound is a blocker or non-blocker of hERG potassium ion channel. These mod- els fit generally satisfactory. The 100 models built with MACCS fingerprints （Model Group A） showed an average accuracy of 90% and an average matthews correlation coefficient （MCC） value of 0.77 on the test sets. The 100 models built with selected MOE descriptors （Model Group B） showed an average accuracy of 89% and an average MCC value of 0.74 on the test sets. Molecular hydrophobicity and lipophilicity were found to be very important factors which lead to block the hERG potassium ion channel. Some other molecular properties such as electrostatic properties, features based on van der Waals surface area, the number of rigid bonds and molecular surface rugosity also played important roles in blocking bERG potassium ion channel.
基金supported by a grant from the National Science and Technology Major Special Project on Major New Drug Innovation of China (Nos. 2012ZX09301002-004 and 2014ZX09507003006-003)
文摘The purpose of this study is to investigate the expression of major potassium channel subtypes in the brain of chronical mild stress (CMS) rats and reveal the effects of fluoxetine on the expression of these channels. Rats were exposed to a variety of unpredictable stress for three weeks and induced anhedonia, lower sucrose preference, locomotor activity and lower body weight The protein expressions were determined by Western blot. CMS significantly increased the expression of Kv2.1 channel in frontal cortex but not in hippocampus, and the expression level was normalized after fluoxetine treatment. the expression of TREK-1 channel was also obviously increased in frontal cortex in CMS rats. Fluoxetine treatment might prevent this increase. However, the expression of Kv3.1 and Kv4.2 channels was considerably decreased in hippocampus after CMS, and was not affected by fluoxetine. These results suggest that different subtypes of potassium channels are associated with the pathophy-siology of depression and that the therapeutical effects of fluoxetine may relate to Kv2.1 and TREK-1 potassium channels. (C) 2015 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. All rights reserved.
文摘Although it has been more than 165 years since the first introduction of modern anesthesia to the clinic, there is surprisingly little understanding about the exact mechanisms by which general anesthetics induce unconsciousness. As a result, we do not know how general anesthetics produce anesthesia at different levels. The main handicap to understanding the mechanisms of general anesthesia is the diversity of chemically unrelated compounds including diethyl ether and halogenated hydrocarbons, gases nitrous oxide, ketamine, propofol, benzodiazepines and etomidate, as well as alcohols and barbiturates. Does this imply that general anesthesia is caused by many different mechanisms? Until now, many receptors, molecular targets and neuronal transmission pathways have been shown to contribute to mechanisms of general anesthesia. Among these molecular targets, ion channels are the most likely candidates for general anesthesia, in particular γ-aminobutyric acid type A, potassium and sodium channels, as well as ion channels mediated by various neuronal transmitters like acetylcholine, amino acids amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid or N-methyl-D-aspartate. In addition, recent studies have demonstrated the involvement in general anesthesia of other ion channels with distinct gating properties suchas hyperpolarization-activated, cyclic- nucleotide-gated channels. The main aim of the present review is to summarize some aspects of current knowledge of the effects of general anesthetics on various ion channels.
基金It is supported by the National Natural science Foundation of China(No.3 9170 2 2 2 )
文摘To study the gating kinetics of voltage dependent K + channel in clonal pheochromocytoma (PC12) cells, the inward currents of K channel in PC12 cells were recorded using cell attached patch clamp technique. The fractal features of the open and closed time distributions were determined. The fractal dimensions and kinetic setpoints for the open and closed durations were estimated. It was found that the fractal dimension D was independent of voltage and the logarithm logA of the setpoint A was inversely proportional to the pipette potential (Vp) for the closed durations. While for the open durations the fractal dimension D was inversely proportional to the pipette potential and the logarithm logA of the setpoint A was independent of voltage. Thus, for this channel the open and closed durations and voltage dependence of the gating could be well described by the fractal model.
基金Suppported by a grant from the Key Research and Development Program of Shaanxi Province Project(No.2018YBXM-SF-12-2)
文摘Objective The expression of HERG in common bone tumors is scarcely reported and there is a lack of dedicated studies.This study aimed to investigated the expression of HERG in several common musculoskeletal tumors.Methods Immunohistochemical staining,RT-PCR,and Western blotting were used to observe HERG expression differences in various tissues and cell lines.Results HERG was differentially expressed in different malignant tumors,both at a differential protein level and localization within tumors.HERG was not expressed in normal bone tissue.The HERG inhibitor E-4031 markedly inhibited the proliferation of osteosarcoma cell lines.Conclusion HERG was highly expressed in malignant tumors.Blocking of HERG can effectively inhibit the proliferation of bone tumors.
文摘Objective： Our group has previously observed that in patients with small-cell lung cancers （SCLCs）, the expression of a tumor antigen, glioma big potassium （gBK） ion channel, is higher at the time of death than when the cancer is first treated by surgical resection. This study aimed to determine whether this dichotomy was common in other potential lung tumor antigens by examining the same patient samples using our more extensive profile analysis of tumor-antigen precursor protein （TAPP）. We then tested the hypothesis that therapeutic intervention may inadvertently cause this increased gBK production. Methods： SCLC samples （eight surgical resections and three autopsy samples） and three control lungs were examined by quantitative real-time polymerase chain reaction for 42 potential TAPPs that represent potential T-cell-mediated immunological targets. Results： Twenty-two TAPP mRNAs displayed the same profile as gBK, i.e., more mRNAs were expressed at autopsy than in their surgical counterparts. B-cyclin and mouse double minute 2, human homolog of PS3-binding protein were elevated in both autopsy and surgical specimens above the normal-lung controls. When HTB119 cells were incubated with doxorubicin, gBK was strongly induced, as confirmed by intracellular flow cytometry with a gBK-specific antibody. Conclusion： Our findings suggested that more immunological targets became available as the tumor responded to chemotherapy and proceeded toward its terminal stages.
基金supported by the National Natural Science Foundation of China,Nos.U2004106 (to WY),81971061 (to JC)the Key Scientific Research Project of Colleges and Universities in Henan Province,No.21A320039 (to WY)。
文摘Thalamic hemorrhage can lead to the development of central post-stroke pain.Changes in histone acetylation levels,which are regulated by histone deacetylases,affect the excitability of neurons surrounding the hemorrhagic area.However,the regulato ry mechanism of histone deacetylases in central post-stroke pain remains unclea r.Here,we show that iron overload leads to an increase in histone deacetylase 2expression in damaged ventral posterolateral nucleus neurons.Inhibiting this increase restored histone H3 acetylation in the Kcna2 promoter region of the voltage-dependent potassium(Kv)channel subunit gene in a rat model of central post-stroke pain,thereby increasing Kcna2expression and relieving central pain.However,in the absence of nerve injury,increasing histone deacetylase 2 expression decreased Kcna2expression,decreased Kv current,increased the excitability of neurons in the ventral posterolateral nucleus area,and led to neuropathic pain symptoms.Moreover,treatment with the iron chelator deferiprone effectively reduced iron overload in the ventral posterolateral nucleus after intracerebral hemorrhage,reversed histone deacetylase 2 upregulation and Kv1.2 downregulation,and alleviated mechanical hypersensitivity in central post-stroke pain rats.These results suggest that histone deacetylase 2 upregulation and Kv1.2 downregulation,mediated by iron overload,are important factors in central post-stroke pain pathogenesis and co uld se rve as new to rgets for central poststroke pain treatment.
文摘A three-state hopping model is established ac-cording to experiments to study permeation of an open-state potassium channel from Streptomyces Lividans (KcsA po-tassium channel). The master equations are used to charac-terize the dynamics of the system. In this model, ion conduc-tion involves transitions of three states, with one three-ion state and two two-ion states in the selectivity filter respec-tively. In equilibrium, the well-known Nernst equation is deduced. It is further shown that the current follows Micha-elis-Menten kinetics in steady state. According to the pa-rameters provided by Nelson, the current-voltage relation-ship is proved to be ohmic and the current-concentration relationship is also obtained reasonably. Additional valida-tion of the model in the characteristic time to reach the steady state for the potassium channel is also discussed. This model lays a possible physical basis for the permeation of ion channel, and opens an avenue for further research.
文摘Background Ketanserin （KT）, a selective serotonin （5-HT） 2-receptor antagonist, reduces peripheral blood pressure by blocking the activation of peripheral 5-HT receptors. In this study electrophysiological method was used to investigate the effect of KT and potassium ion on Kv1.3 potassium channels and explore the role of blocker KT in the alteration of channel kinetics contributing to the potassium ion imbalances. Methods Kv1.3 channels were expressed in xenopus oocytes, and currents were measured using the two-microelectrode voltage-clamp technique. Results KCI made a left shift of activation and an inactivation curve of Kv1.3 current and accelerated the activation and inactivation time constant. High extracellular [K^＋] attenuated the blockade effect of KT on Kv1.3 channels. In the presence of KT and KCI the activation and inactivation time constants were not influenced significantly no matter what was administered first. KT did not significantly inhibit Kv1.3 current induced by tetraethylammonium （TEA）. Conclusions KT is a weak blocker of Kv1.3 channels at different concentrations of extracellular potassium and binds to the intracellular side of the channel pore. The inhibitor KT of ion channels is not fully effective in clinical use because of high [K^＋]. and other electrolyte disorders.
