Ion channels modulate cellular excitability by regulating ionic fluxes across biological membranes.Pathogenic mutations in ion channel genes give rise to epileptic disorders that are among the most frequent neurologic...Ion channels modulate cellular excitability by regulating ionic fluxes across biological membranes.Pathogenic mutations in ion channel genes give rise to epileptic disorders that are among the most frequent neurological diseases affecting millions of individuals worldwide.Epilepsies are trigge red by an imbalance between excitatory and inhibitory conductances.However,pathogenic mutations in the same allele can give rise to loss-of-function and/or gain-of-function va riants,all able to trigger epilepsy.Furthermore,certain alleles are associated with brain malformations even in the absence of a clear electrical phenotype.This body of evidence argues that the underlying epileptogenic mechanisms of ion channels are more diverse than originally thought.Studies focusing on ion channels in prenatal cortical development have shed light on this apparent paradox.The picture that emerges is that ion channels play crucial roles in landmark neurodevelopmental processes,including neuronal migration,neurite outgrowth,and synapse formation.Thus,pathogenic channel mutants can not only cause epileptic disorders by alte ring excitability,but further,by inducing morphological and synaptic abnormalities that are initiated during neocortex formation and may persist into the adult brain.展开更多
Fibromyalgia is characterized by the primary symptomsof persistent diffuse pain, fatigue, sleep disturbance and cognitive dysfunction. Persistent pain conditions, such as fibromyalgia, are often refractory to current ...Fibromyalgia is characterized by the primary symptomsof persistent diffuse pain, fatigue, sleep disturbance and cognitive dysfunction. Persistent pain conditions, such as fibromyalgia, are often refractory to current available therapies. An involvement of K^+ channels in the pathophysiology of fibromyalgia is emerging and supported by drug treatments for this condition exhibiting action at these molecular processes. K^+ channels constitute potential novel target candidates for pain therapy offering peripheral and/or central actions. The Kv7 channel activators, flupirtine and retigabine, have exhibited pharmacological profiles compatible to the requirements needed for use as a therapeutic approach to fibromyalgia. Clinical trials to address the multidimensional challenges of fibromyalgia with flupirtine and retigabine will provide important insight to the role of K^+ channels in this condition.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
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
This study aimed to comprehend the largely unknown role of voltage-gated potassium channel 1.3 （Kvl.3） in the phagocytic function of macrophages. We found that blocking of the Kv 1.3 channel with 100 pmol L 1 Sticho...This study aimed to comprehend the largely unknown role of voltage-gated potassium channel 1.3 （Kvl.3） in the phagocytic function of macrophages. We found that blocking of the Kv 1.3 channel with 100 pmol L 1 Stichodactyla helianthus neurotoxin （ShK） enhanced the phagocytic capacities of both resting and lipopolysaccharide （LPS）-stimulated RAW264.7 macrophages in the chicken erythrocyte system. In the fluorescein isothiocyanate （FITC）-labeled Escherichia coli k-12 system, ShK increased the phagocytic capacities of resting RAW264.7 cells, but not of the LPS-stimulated cells, as LPS alone stimulated almost satu- rated phagocytosis of the macrophages. ShK increased the nitric oxide （NO） production in LPS-activated cells, but not in rest- ing RAW264.7 cells. There was no effect of ShK alone on the cytokine secretions in resting RAW264.7 cells, but it suppressed IL-113 secretion in LPS-stimulated RAW264.7 cells. At a concentration of 100 pmol L 1, ShK did not affect the viability of the tested cells. Kv 1.3 was expressed in RAW264.7 cells; this expression was downregulated by LPS, but significantly upregulat- ed by disrupting caveolin-dependent endocytosis with filipin III. In addition, cytochalasin D, an inhibitor of actin polymeriza- tion, did not affect the Kvl.3 expression. Thus, blocking of the Kvl.3 channel enhances the phagocytic capacity and NO pro- duction of this cell line. Our results suggest that Kv 1.3 channel serves as a negative regulator of phagocytosis in macrophages and can therefore be a potential target in the treatment of macrophage dysfunction.展开更多
Background The cell layer of the ciliary epithelium is responsible for aqueous humor secretion and maintenance. Ion channels play an important role in these processes. The main aim of this study was to determine wheth...Background The cell layer of the ciliary epithelium is responsible for aqueous humor secretion and maintenance. Ion channels play an important role in these processes. The main aim of this study was to determine whether the well-characterized members of the Kvl family （Kv1.3） contribute to the Kv currents in ciliary epithelium. Methods New Zealand White rabbits were maintained in a 12 hours light/dark cycle. Ciliary epithelium samples were isolated from the rabbits. We used Western blotting and immunocytochemistry to identify the expression and location of a voltage-gated potassium channel Kvl.3 in ciliary body epithelium. Membrane potential change after adding of Kvl.3 inhibitor margatoxin （MgTX） was observed with a fluorescence method. Results Western blotting and immunocytochemical studies showed that the Kv1.3 protein expressed in pigment ciliary epithelium and nonpigment ciliary epithelium, however it seemed to express more in the apical membrane of the nonpigmented epithelial cells. One nmol/L margatoxin, a specific inhibitor of Kv1.3 channels caused depolarization of the cultured nonpigmented epithelium （NPE） membrane potential. The cytosolic calcium increased after NPE cell depolarization, this increase of cytosolic calcium was partially blocked by 12.5 μmol/L dantrolene and 10 μmol/L nifedipine. These observations suggest that Kv1.3 channels modulate ciliary epithelium potential and effect calcium dependent mechanisms. Conclusion Kv1.3 channels contribute to K＋ efflux at the membrane of rabbit ciliary epithelium.展开更多
Kv1.5 potassium channel is reported as a potent and safe target for atrial fibrillation.CPUY11018 was proved it had moderate inhibition of Kv1.5.In order to improve the stability of CPUY11018,and investigate the struc...Kv1.5 potassium channel is reported as a potent and safe target for atrial fibrillation.CPUY11018 was proved it had moderate inhibition of Kv1.5.In order to improve the stability of CPUY11018,and investigate the structure-activity relationship,4 series of benzamide derivatives were synthesized and evaluated.Among them,8c is a most potent inhibitor of Kv1.5.展开更多
基金NJ Governor’s Council for Medical Research and Treatment of Autism predoctoral fellowship (CAUT23AFP015) to ABNational Science Foundation grant (2030348) to FS。
文摘Ion channels modulate cellular excitability by regulating ionic fluxes across biological membranes.Pathogenic mutations in ion channel genes give rise to epileptic disorders that are among the most frequent neurological diseases affecting millions of individuals worldwide.Epilepsies are trigge red by an imbalance between excitatory and inhibitory conductances.However,pathogenic mutations in the same allele can give rise to loss-of-function and/or gain-of-function va riants,all able to trigger epilepsy.Furthermore,certain alleles are associated with brain malformations even in the absence of a clear electrical phenotype.This body of evidence argues that the underlying epileptogenic mechanisms of ion channels are more diverse than originally thought.Studies focusing on ion channels in prenatal cortical development have shed light on this apparent paradox.The picture that emerges is that ion channels play crucial roles in landmark neurodevelopmental processes,including neuronal migration,neurite outgrowth,and synapse formation.Thus,pathogenic channel mutants can not only cause epileptic disorders by alte ring excitability,but further,by inducing morphological and synaptic abnormalities that are initiated during neocortex formation and may persist into the adult brain.
文摘Fibromyalgia is characterized by the primary symptomsof persistent diffuse pain, fatigue, sleep disturbance and cognitive dysfunction. Persistent pain conditions, such as fibromyalgia, are often refractory to current available therapies. An involvement of K^+ channels in the pathophysiology of fibromyalgia is emerging and supported by drug treatments for this condition exhibiting action at these molecular processes. K^+ channels constitute potential novel target candidates for pain therapy offering peripheral and/or central actions. The Kv7 channel activators, flupirtine and retigabine, have exhibited pharmacological profiles compatible to the requirements needed for use as a therapeutic approach to fibromyalgia. Clinical trials to address the multidimensional challenges of fibromyalgia with flupirtine and retigabine will provide important insight to the role of K^+ channels in this condition.
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.
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.
基金supported by the National Key Basic Research Program of China(2011CB93350)National Natural Science Foundation of China(31171088,31471126,81470540,81300139)
文摘This study aimed to comprehend the largely unknown role of voltage-gated potassium channel 1.3 （Kvl.3） in the phagocytic function of macrophages. We found that blocking of the Kv 1.3 channel with 100 pmol L 1 Stichodactyla helianthus neurotoxin （ShK） enhanced the phagocytic capacities of both resting and lipopolysaccharide （LPS）-stimulated RAW264.7 macrophages in the chicken erythrocyte system. In the fluorescein isothiocyanate （FITC）-labeled Escherichia coli k-12 system, ShK increased the phagocytic capacities of resting RAW264.7 cells, but not of the LPS-stimulated cells, as LPS alone stimulated almost satu- rated phagocytosis of the macrophages. ShK increased the nitric oxide （NO） production in LPS-activated cells, but not in rest- ing RAW264.7 cells. There was no effect of ShK alone on the cytokine secretions in resting RAW264.7 cells, but it suppressed IL-113 secretion in LPS-stimulated RAW264.7 cells. At a concentration of 100 pmol L 1, ShK did not affect the viability of the tested cells. Kv 1.3 was expressed in RAW264.7 cells; this expression was downregulated by LPS, but significantly upregulat- ed by disrupting caveolin-dependent endocytosis with filipin III. In addition, cytochalasin D, an inhibitor of actin polymeriza- tion, did not affect the Kvl.3 expression. Thus, blocking of the Kvl.3 channel enhances the phagocytic capacity and NO pro- duction of this cell line. Our results suggest that Kv 1.3 channel serves as a negative regulator of phagocytosis in macrophages and can therefore be a potential target in the treatment of macrophage dysfunction.
文摘Background The cell layer of the ciliary epithelium is responsible for aqueous humor secretion and maintenance. Ion channels play an important role in these processes. The main aim of this study was to determine whether the well-characterized members of the Kvl family （Kv1.3） contribute to the Kv currents in ciliary epithelium. Methods New Zealand White rabbits were maintained in a 12 hours light/dark cycle. Ciliary epithelium samples were isolated from the rabbits. We used Western blotting and immunocytochemistry to identify the expression and location of a voltage-gated potassium channel Kvl.3 in ciliary body epithelium. Membrane potential change after adding of Kvl.3 inhibitor margatoxin （MgTX） was observed with a fluorescence method. Results Western blotting and immunocytochemical studies showed that the Kv1.3 protein expressed in pigment ciliary epithelium and nonpigment ciliary epithelium, however it seemed to express more in the apical membrane of the nonpigmented epithelial cells. One nmol/L margatoxin, a specific inhibitor of Kv1.3 channels caused depolarization of the cultured nonpigmented epithelium （NPE） membrane potential. The cytosolic calcium increased after NPE cell depolarization, this increase of cytosolic calcium was partially blocked by 12.5 μmol/L dantrolene and 10 μmol/L nifedipine. These observations suggest that Kv1.3 channels modulate ciliary epithelium potential and effect calcium dependent mechanisms. Conclusion Kv1.3 channels contribute to K＋ efflux at the membrane of rabbit ciliary epithelium.
基金National High-tech R&D Program of China (863Program,Grant No. 2007AA02Z307)National Major Science andTechnology Project of China (Grant No. 2009ZX09103-088 and 2009ZX09501-003)
文摘Kv1.5 potassium channel is reported as a potent and safe target for atrial fibrillation.CPUY11018 was proved it had moderate inhibition of Kv1.5.In order to improve the stability of CPUY11018,and investigate the structure-activity relationship,4 series of benzamide derivatives were synthesized and evaluated.Among them,8c is a most potent inhibitor of Kv1.5.
