This article discusses a study by Li et al,which investigates the role of the microglial voltage-gated proton channel 1(Hv1)in diabetes-related cognitive decline.The authors showed that Hv1 is upregulated in the corpu...This article discusses a study by Li et al,which investigates the role of the microglial voltage-gated proton channel 1(Hv1)in diabetes-related cognitive decline.The authors showed that Hv1 is upregulated in the corpus callosum of diabetic mice and that its knockout improves working memory,reduces microglial production of interleukin-1βand tumour necrosis factor alpha,and decreases apoptosis of oligodendrocyte progenitor cells.Furthermore,electron microscopy revealed that the myelin thickness and the g-ratio were preserved in Hv1 knockout mice,remaining within normal limits.In addition,Hv1 knockdown mitigated interleukin-1βsecretion and suppressed ferroptosis markers(ferritin heavy chain/ferritin light chain,CCAAT/enhancer binding protein homologous protein,glucose-regulated protein 78,etc.)in vitro,suggesting the involvement of an Hv1-reactive oxygen species-glucose-regulated protein 78 axis in diabetic demyelination.We highlight the translational implications of these findings and recommend future studies employing microglia-specific Hv1 deletion models,longitudinal cognitive assessments and preclinical evaluation of pharmacological Hv1 inhibitors.展开更多
BACKGROUND Diabetes is associated with increased cognitive decline and dementia due to the loss of myelinated nerve fiber function,which is linked to oligodendrocyte dysfunction.The voltage-gated proton channel 1(Hv1)...BACKGROUND Diabetes is associated with increased cognitive decline and dementia due to the loss of myelinated nerve fiber function,which is linked to oligodendrocyte dysfunction.The voltage-gated proton channel 1(Hv1)is important for the cellular proton extrusion machinery.However,its role in regulating diabetesinduced cognitive dysfunction is unclear.AIM To investigate the role of Hv1 in cognitive impairment induced by diabetes and its potential mechanisms,focusing on neuroinflammation,oligodendrocyte apoptosis,and axonal demyelination.METHODS A diabetes model was established by administering a high-fat diet and streptozotocin injections in mice.Hv1 knockout(KO)and wild-type mice were used to evaluate cognitive function via behavioral tests and neuroinflammation using immunofluorescence.Oligodendrocyte apoptosis was assessed with the terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay, and axonal demyelination wasanalyzed using electron microscopy.RESULTSHv1 expression was significantly increased in the corpus callosum of diabetic mice. Hv1 KO alleviated cognitiveimpairment, reduced oligodendrocyte apoptosis, and decreased the expression of inflammatory factors, includinginterleukin-1 and tumor necrosis factor-α, in diabetic mice. Electron microscopy revealed a reduction in myelinthickness and an increased g-ratio in diabetic mice, which were reversed by Hv1 KO.CONCLUSIONHv1 plays a role in diabetes-induced cognitive dysfunction by modulating neuroinflammation and myelinintegrity. Hv1 KO demonstrates therapeutic potential in mitigating diabetes-related cognitive decline andassociated complications.展开更多
Voltage-gated ion channels(VGICs) are central to cellular excitation, orchestrating skeletal and cardiac muscle contractions and enabling neural signal transduction. Among these, voltage-gated potassium(Kv) channels a...Voltage-gated ion channels(VGICs) are central to cellular excitation, orchestrating skeletal and cardiac muscle contractions and enabling neural signal transduction. Among these, voltage-gated potassium(Kv) channels are particularly significant in cardiac electrophysiology, especially during the repolarization phase of the cardiac action potential. In cardiac myocytes, Kv channels are integral to a multitude of sophisticated functions, including electrical conduction. Despite their importance, research on Kv channels in the context of cardiovascular diseases is limited. This review offers a comprehensive summary of the structural complexities of Kv channels, delineating the regulatory mechanisms involved in channel gating, expression, and membrane localization. Additionally, we examine the role of different Kv α-subunits in modulating Kv channels and their impact on cardiac remodeling, and assess the potential of targeting Kv channels for the development of anti-arrhythmic therapies.展开更多
OBJECTIVE: To examine the effect of electroacupuncture(EA) at bilateral Neiguan(PC 6) on voltage-gated Na+currents(INa) and channels(Nav) in ischemic ventricular myocytes.METHODS: EA serum was prepared from six male a...OBJECTIVE: To examine the effect of electroacupuncture(EA) at bilateral Neiguan(PC 6) on voltage-gated Na+currents(INa) and channels(Nav) in ischemic ventricular myocytes.METHODS: EA serum was prepared from six male adult Sprague-Dawley rats that had received EA at bilateral Neiguan(PC 6). Eighteen ventricular myocytes were prepared from six SD rats using an enzymolysis approach. Myocardial ischemia was mimicked by perfusion of ischemic solution. Whole-cell patch-clamping was used to record three currents evoked from isolated cells. The first current was the control, and recorded in absence of ischemic solution current. The second was the ischemic current,and recorded after perfusion of ischemic solution for 5 min, while the EA current was last, and recorded after perfusion of EA serum for 5 min. Navkinetic curves were fitted using related formulas.RESULTS: Compared with those in controls, in the presence of ischemic solution, peak amplitudes of INasignificantly increased from ﹣40 m V to +30 m V,and half-maximal inactivation potentials of Navincreased significantly, while half-maximal activation potentials, slope factors and the recovery time from inactivation to activation of Navwere unchanged. Compared with those in the ischemic solution, in the presence of EA serum, peak ischemic current amplitudes significantly reduced from ﹣40m V to + 40 m V, and half-maximal inactivation potentials were restored, while half-maximal activation potentials, slope factors and the recovery time from inactivation to activation of Navwere unchanged.CONCLUSION: EA at bilateral Neiguan(PC 6) can reduce enhanced INavia restoration of delayed Navinactivation in ischemic ventricular myocytes.展开更多
Objective To examine the effect of deglycosylation on gating properties of rNav1.3. Methods rNav1.3 was expressed in Xenopus oocyte, with glycosylation inhibition by using tunicamycin. Two-electrode voltage clamp was ...Objective To examine the effect of deglycosylation on gating properties of rNav1.3. Methods rNav1.3 was expressed in Xenopus oocyte, with glycosylation inhibition by using tunicamycin. Two-electrode voltage clamp was employed to record the whole-cell sodium current and data were analyzed by Origin software. Those of glycosylated rNav1.3 were kept as control. Results Compared with glycosylated ones, the steady-state activation curve of deglycosylated rNav1.3 was positively shifted by about 10 mV, while inactivation curve was negatively shifted by about 8 mV. Conclusion Glycosylation altered the gating properties of rNav 1.3 and contributed to the functional diversity.展开更多
Voltage-gated sodium channels （Navs） play an important role in human pain sensation. However, the expression and role of Nav subtypes in native human sensory neurons are unclear. To address this issue, we obtained h...Voltage-gated sodium channels （Navs） play an important role in human pain sensation. However, the expression and role of Nav subtypes in native human sensory neurons are unclear. To address this issue, we obtained human dorsal root ganglion （hDRG） tissues from healthy donors. PCR analysis of seven DRG-expressed Nav subtypes revealed that the hDRG has higher expression of Navl.7 （,-~ 50% of total Nav expression） and lower expres- sion of Navl.8 （~ 12%）, whereas the mouse DRG has higher expression of Nav 1.8 （- 45%） and lower expression of Navl.7 （- 18%）. To mimic Nav regulation in chronic pain, we treated hDRG neurons in primary cultures with paclitaxel （0.1-1 μmol/L） for 24 h. Paclitaxel increased the Navl.7 but not Navl.8 expression and also increased the transient Na＋ currents and action potential firing frequency in small-diameter （〈50 ~tm） hDRG neurons. Thus, the hDRG provides a translational model in which to study ＂human pain in a dish＂ and test new pain therapeutics.展开更多
Interleukin-6 has been shown to be involved in nerve injury and nerve regeneration, but the effects of long-term administration of high concentrations of interleukin-6 on neurons in the central nervous system is poorl...Interleukin-6 has been shown to be involved in nerve injury and nerve regeneration, but the effects of long-term administration of high concentrations of interleukin-6 on neurons in the central nervous system is poorly understood. This study investigated the effects of 24 hour expo-sure of interleukin-6 on cortical neurons at various concentrations （0.1, 1, 5 and 10 ng/mL） and the effects of 10 ng/mL interleukin-6 exposure to cortical neurons for various durations （2, 4, 8, 24 and 48 hours） by studying voltage-gated Na＋ channels using a patch-clamp technique. Volt-age-clamp recording results demonstrated that interleukin-6 suppressed Na＋ currents through its receptor in a time- and dose-dependent manner, but did not alter voltage-dependent activation and inactivation. Current-clamp recording results were consistent with voltage-clamp recording results. Interleukin-6 reduced the action potential amplitude of cortical neurons, but did not change the action potential threshold. The regulation of voltage-gated Na＋channels in rat corti-cal neurons by interleukin-6 is time- and dose-dependent.展开更多
Activin A, which was first described in 1986, has been shown to maintain hippocampal neuronal survival. Activin A increases intracellular free Ca2＋ via L-type Ca2＋ channels. Our previous study showed that activin A ...Activin A, which was first described in 1986, has been shown to maintain hippocampal neuronal survival. Activin A increases intracellular free Ca2＋ via L-type Ca2＋ channels. Our previous study showed that activin A promotes neurite growth of dorsal root ganglia in embryonic chickens and inhibits nitric oxide secretion. The present study demonstrated for the first time that activin A could maintain cerebral cortex neuronal survival in vitro for a long period, and that activin A was shown to increase voltage-gated Na＋ current （/Na） in Neuro-2a cells, which was recorded by patch clamp technique. The present study revealed a novel mechanism for activin A, as well as the influence of activin A on neurons by regulating expressions of vasoactive intestine peptide and inducible nitric oxide synthase.展开更多
Voltage-gated sodium channels (VGSCs) play a fundamental role in controlling cellular excitability,and their abnormal activity is related to several pathological processes,including cardiac arrhythmias,epilepsy,neurod...Voltage-gated sodium channels (VGSCs) play a fundamental role in controlling cellular excitability,and their abnormal activity is related to several pathological processes,including cardiac arrhythmias,epilepsy,neurodegenerative diseases,spasticity and chronic pain.In particular,chronic visceral pain,the central symptom of functional gastrointestinal disorders such as irritable bowel syndrome,is a serious clinical problem that affects a high percentage of the world population.In spite of intense research efforts and after the dedicated decade of pain control and research,there are not many options to treat chronic pain conditions.However,there is a wealth of evidence emerging to give hope that a more refined approach may be achievable.By using electronic databases,available data on structural and functional properties of VGSCs in chronic pain,particularly functional gastrointestinal hypersensitivity,were reviewed.We summarize the involvement and molecular bases of action of VGSCs in the pathophysiology of several organic and functionalgastrointestinal disorders.We also describe the efficacy of VGSC blockers in the treatment of these neurological diseases,and outline future developments that may extend the therapeutic use of compounds that target VGSCs.Overall,clinical and experimental data indicate that isoform-specific blockers of these channels or targeting of their modulators may provide effective and novel approaches for visceral pain therapy.展开更多
Atrial fibrillation(AF)is the most common cardiac arrhythmia worldwide.The prevalence of the disease increases with age,strongly implying an age-related process underlying the pathology.At a time when people are livin...Atrial fibrillation(AF)is the most common cardiac arrhythmia worldwide.The prevalence of the disease increases with age,strongly implying an age-related process underlying the pathology.At a time when people are living longer than ever before,an exponential increase in disease prevalence is predicted worldwide.Hence unraveling the underlying mechanics of the disease is paramount for the development of innovative treatment and prevention strategies.The role of voltage-gated sodium channels is fundamental in cardiac electrophysiology and may provide novel insights into the arrhythmogenesis of AF.Na_v1.5 is the predominant cardiac isoform,responsible for the action potential upstroke.Recent studies have demonstrated that Na_v1.8(an isoform predominantly expressed within the peripheral nervous system)is responsible for cellular arrhythmogenesis through the enhancement of pro-arrhythmogenic currents.Animal studies have shown a decline in Na_v1.5 leading to a diminished action potential upstroke during phase 0.Furthermore,the study of human tissue demonstrates an inverse expression of sodium channel isoforms;reduction of Na_v1.5 and increase of Na_v1.8 in both heart failure and ventricular hypertrophy.This strongly suggests that the expression of voltage-gated sodium channels play a crucial role in the development of arrhythmias in the diseased heart.Targeting aberrant sodium currents has led to novel therapeutic approaches in tackling AF and continues to be an area of emerging research.This review will explore how voltage-gated sodium channels may predispose the elderly heart to AF through the examination of laboratory and clinical based evidence.展开更多
Voltage-gated sodium channels （VGSCs） are known to be involved in the initiation and progression of many malignancies, and the different subtypes of VGSCs play important roles in the metastasis cascade of many tumor...Voltage-gated sodium channels （VGSCs） are known to be involved in the initiation and progression of many malignancies, and the different subtypes of VGSCs play important roles in the metastasis cascade of many tumors. This study investigated the functional expression of Nav1.5 and its effect on invasion behavior of human breast cancer cell line MDA-MB-231. The mRNA and protein expression of Nav1.5 was detected by real time PCR, Western Blot and immunofluorescence. The effects of Nav1.5 on cell proliferation, migration and invasion were respectively assessed by MTT and Transwell. The effects of Nav1.5 on the secretion of matrix metalloproteases （MMPs） by MDA-MB-231 were analyzed by RT-PCR. The over-expressed Nav 1.5 was present on the membrane of MDA-MB-231 cells. The invasion ability in vitro and the MMP-9 mRNA expression were respectively decreased to （47.82±0.53）% and （43.97±0.64）% （P〈0.05） respectively in MDA-MB-23 t cells treated with VGSCs specific inhibitor tetrodotoxin （TTX） by blocking Navl.5 activity. It was concluded that Navl.5 functional expression potentiated the invasive behavior of human breast cancer cell line MDA-MB-231 by increasing the secretion of MMP-9.展开更多
Hv1 is the only voltage-gated proton-selective channel in mammalian cells.It contains a conserved voltage-sensor domain,shared by a large class of voltage-gated ion channels,but lacks a pore domain.Its primary role is...Hv1 is the only voltage-gated proton-selective channel in mammalian cells.It contains a conserved voltage-sensor domain,shared by a large class of voltage-gated ion channels,but lacks a pore domain.Its primary role is to extrude protons from the cytoplasm upon pH reduction and membrane depolarization.The best-known function of Hv1 is the regulation of cytosolic pH and the nicotinamide adenine dinucleotide phosphate oxidase-dependent production of reactive oxygen species.Accumulating evidence indicates that Hv1 is expressed in nervous systems,in addition to immune cells and others.Here,we summarize the molecular properties,distribution,and physiological functions of Hv1 in the peripheral and central nervous systems.We describe the recently discovered functions of Hv1 in various neurological diseases,including brain or spinal cord injury,ischemic stroke,demyelinating diseases,and pain.We also summarize the current advances in the discovery and application of Hv1-targeted small molecules in neurological diseases.Finally,we discuss the current limitations of our understanding of Hv1 and suggest future research directions.展开更多
Chlorogenic acid（5-caffeoylquinic acid, CGA） is a phenolic compound that is found ubiquitously in plants, fruits and vegetables and is formed via the esterification of caffeic acid and quinic acid. In addition to it...Chlorogenic acid（5-caffeoylquinic acid, CGA） is a phenolic compound that is found ubiquitously in plants, fruits and vegetables and is formed via the esterification of caffeic acid and quinic acid. In addition to its notable biological functions against cardiovascular diseases, type-2 diabetes and inflammatory conditions, CGA was recently hypothesized to be an alternative for the treatment of neurological diseases such as Alzheimer＇s disease and neuropathic pain disorders. However, its mechanism of action is unclear.Voltage-gated potassium channel（Kv） is a crucial factor in the electro-physiological processes of sensory neurons. Kv has also been identified as a potential therapeutic target for inflammation and neuropathic pain disorders. In this study, we analysed the effects of CGA on the two main subtypes of Kv in trigeminal ganglion neurons, namely, the IK,Aand IK,Vchannels. Trigeminal ganglion（TRG）neurons were acutely disassociated from the rat TRG, and two different doses of CGA（0.2 and 1 mmol·L21） were applied to the cells.Whole-cell patch-clamp recordings were performed to observe alterations in the activation and inactivation properties of the IK,Aand IK,Vchannels. The results demonstrated that 0.2 mmol·L21CGA decreased the peak current density of IK,A. Both 0.2 mmol·L21and1 mmol·L21CGA also caused a significant reduction in the activation and inactivation thresholds of IK,Aand IK,V. CGA exhibited a strong effect on the activation and inactivation velocities of IK,Aand IK,V. These findings provide novel evidence explaining the biological effects of CGA, especially regarding its neurological effects.展开更多
AIM： To investigate the action of genistein （GST）, a broad spectrum tyrosine kinase inhibitor, on voltagegated potassium channels in guinea pig proximal colon smooth muscle cells. METHODS： Smooth muscle cells in g...AIM： To investigate the action of genistein （GST）, a broad spectrum tyrosine kinase inhibitor, on voltagegated potassium channels in guinea pig proximal colon smooth muscle cells. METHODS： Smooth muscle cells in guinea pig proximal colon were enzymatically isolated. Nystatin-perforated whole cell patch clamp technique was used to record potassium currents including fast transient outward current （Ikto） and delayed rectifier current （Ikdr）, tWO of which were isolated pharmacologically with 10 mmol/L tetraethylammonium or 5 mmol/L 4-aminopyridine. Contamination of calcium-dependent potassium currents was minimized with no caldum and 0.2 mmol/L CdCl2 in an external solution. RESULTS： GST （10-100 μmol/L） reversibly and dosedependently reduced the peak amplitude of Ikto with an IC50 value of 22.0±6.9 μmol/L. To a lesser extent, Ikdr, was also inhibited in both peak current and sustained current. GST could not totally block the outward potassium current as a fraction of the outWard potassium current, which was insensitive to GST. GST had no effect on the steady-state activation （n =6） and inactivation kinetics （n =6） of Ikto. Sodium orthovanadate （1 retool/L）, a potent inhibitor of tyrosine phosphatase, significantly inhibited GST-induced inhibition （P〈 0.05）. CONCLUSION： GST can dose-dependently and reversibly block voltage-gated potassium channels in guinea pig proximal colon smooth muscle cells.展开更多
Voltage-gated sodium channels(VGSCs)are transiently expressed in cochlear hair cells before hearing onset and play an indispensable role in shaping spontaneous activity.In this study,we showed that Na^+currents shaped...Voltage-gated sodium channels(VGSCs)are transiently expressed in cochlear hair cells before hearing onset and play an indispensable role in shaping spontaneous activity.In this study,we showed that Na^+currents shaped the spontaneous action potentials in developing mouse inner hair cells(IHCs)by decreasing the time required for the membrane potential to reach the action-potential threshold.In immature IHCs,we identified 9 known VGSC subtypes(Navl.la-l.9ot),among which Navl.7a was the most highly expressed subtype and the main contributor to Na+currents in developing hair cells.Electrophysiological recordings of two cochlea-specific Navi.7 variants(CbmNavl.7a and CbmNavl.7b)revealed a novel loss-of-function mutation(C934R)at the extracellular linker between segments 5 and 6 of domain II.In addition,post-transcriptional modification events,such as alternative splicing and RNA editing,amended the gating properties and kinetic features of CbmNavl.7a(C934).These results provide molecular and functional characteristics of VGSCs in mammalian IHCs and their contributions to spontaneous physiological activity during cochlear maturation.展开更多
Voltage-gated sodium(Nav)channels are critical players in the generation and propagation of action potentials by triggering membrane depolarization.Mutations in Nav channels are associated with a variety of channelopa...Voltage-gated sodium(Nav)channels are critical players in the generation and propagation of action potentials by triggering membrane depolarization.Mutations in Nav channels are associated with a variety of channelopathies,which makes them relevant targets for pharmaceutical intervention.Sofar,the cryoelectron microscopic structure of the human Nav 1.2,Nav 1.4,and Nav 1.7 has been reported,which sheds light on the molecular basis of functional mechanism of Nav channels and provides a path toward structure-based drug discovery.In this review,we focus on the recent advances in the structure,molecular mechanism and modulation of Nav channels,and state updated sodium channel blockers for the treatment of pathophysiology disorders and briefly discuss where the blockers may be developed in the future.展开更多
Objective. To investigate the properties of voltage-gated sodium (Na+) channels in developing auditoryneurons during early postnatal stages in the mammalian central nervous system.Methods. Using the whole-cell voltage...Objective. To investigate the properties of voltage-gated sodium (Na+) channels in developing auditoryneurons during early postnatal stages in the mammalian central nervous system.Methods. Using the whole-cell voltage-clamp technique, we have studied changes in the electrophysi-ological properties of Na+ channels in the principal neurons of the medial nucleus of the trapezoid body (MNTB).Results. We found that MNTB neurons already express functional Na+ channels at postnatal day 1 (P1),and that channel density begins to increase at P5 when the neurons receive synaptic innervation andreach its maximum (～3 fold) at P11 when functional hearing onsets. These changes were paralleled byan age-dependent acceleration in both inactivation and recovery from inactivation. In contrast, there wasvery little alteration in the voltage-dependence of inactivation.Conclusion. These profound changes in the properties of voltage-gated Na+ channels may increase theexcitability of MNTB neurons and enhance their phase-locking fidelity and capacity during high-frequencysynaptic transmission.展开更多
Objective The purpose of our study is to observe the voltage-gated potassium channel Kvl.3 expressed on CD4＋CD28~ T cells from the peripheral blood of acute coronary syndrome （ACS） patients by the patch clamp techn...Objective The purpose of our study is to observe the voltage-gated potassium channel Kvl.3 expressed on CD4＋CD28~ T cells from the peripheral blood of acute coronary syndrome （ACS） patients by the patch clamp technique. Methods Kvl.3 potassium channels expression from 17 patients with ACS and 11 healthy age-match controls was detected in single cell（CD4＋CD28null T cells and CD4＋CD28＋T cells） by fluorescence mieroscopy and patch clamp. Results The percentage of CD4＋CD28mullT cells was higher in the ACS patients [（6.97±2.05）%] than that in the controls [（1.38±0.84）%, P〈0.05]. The concentration of hsCRP was directly correlated with the number of the CD4~CD28nul~ T cells in the ACS patients （r=0.52, P〈0,05）. The conductance （6.89±1.17ns vs 3.36±0.66ns）, dens （1.95±0.80 μm2 vs 1.13±0.57 μm2） and numbers （574.5±97.6 n/cell vs. 280.3±55.3 n/cell） of the Kv1.3 channels on the CIM＋CD28null T cells were significantly higher than those on the CD4＋CD28＋ T cells （all P〈0.01） in ACS patients, but were similar on CD4＋CD28＋T betweenACS patients and controls. Conclusion The CD4＋CD28nullT cells and the numbers of Kvl.3 channels on the CD4＋CD28nullT cells from patients with ACS are significantly upregulated and might contribute to the pathogenesis of ACS （d Geriatr Cardio12010; 7：40-46）.展开更多
Saldigones A-C(1,3,4),three new isoprenylated flavonoids with diverse flavanone,pterocarpan,and isoflavanone architec-tures,were characterized from the roots of Salvia digitaloides,together with a known isoprenylated ...Saldigones A-C(1,3,4),three new isoprenylated flavonoids with diverse flavanone,pterocarpan,and isoflavanone architec-tures,were characterized from the roots of Salvia digitaloides,together with a known isoprenylated flavanone(2).Notably,it’s the first report of isoprenylated flavonoids from Salvia species.The structures of these isolates were elucidated by extensive spectroscopic analysis.All of the compounds were evaluated for their activities on Cav3.1 low voltage-gated Ca^(2+)channel(LVGCC),of which 2 strongly and dose-dependently inhibited Cav3.1 peak current.展开更多
Introduction: Antibodies to voltage-gated potassium channels have been implicated in causing a host of peripheral and central nervous system disorders. However, the presence of these antibodies has not been previously...Introduction: Antibodies to voltage-gated potassium channels have been implicated in causing a host of peripheral and central nervous system disorders. However, the presence of these antibodies has not been previously associated with motor neuropathy. We describe the first case of acquired motor neuron disease associated with voltage-gated potas-sium channel antibodies. Case Report: The patient is an 81-year-old female who developed signs and symptoms of an idiopathic motor neuron disease. The patient was found to have increased antibodies to voltage-gated potassium chan-nels in the absence of a known metastatic or autoimmune process. Magnetic resonance imaging of the cervical spine demonstrated increased signal in the anterior horn regions of the cervical and upper thoracic spinal cord on T2-weighted imaging. The patient’s disease progression was refractory to both intravenous immunoglobulin and ster-oid therapy. Conclusion: Voltage-gated potassium channels may be causal or simply associated with motor neuron disease;this relationship needs to be elucidated. Testing for these antibodies may be warranted in cases of idiopathic rapidly progressing motor neuron disease.展开更多
基金Supported by the Top-Level Talents Support Program of Yangzhou University“Lv Yang Jin Feng”Outstanding Doctor of Yangzhou,No.YZLYJFJH2023YXBS169and Natural Science Foundation of Jiangsu Province,No.BK20240907。
文摘This article discusses a study by Li et al,which investigates the role of the microglial voltage-gated proton channel 1(Hv1)in diabetes-related cognitive decline.The authors showed that Hv1 is upregulated in the corpus callosum of diabetic mice and that its knockout improves working memory,reduces microglial production of interleukin-1βand tumour necrosis factor alpha,and decreases apoptosis of oligodendrocyte progenitor cells.Furthermore,electron microscopy revealed that the myelin thickness and the g-ratio were preserved in Hv1 knockout mice,remaining within normal limits.In addition,Hv1 knockdown mitigated interleukin-1βsecretion and suppressed ferroptosis markers(ferritin heavy chain/ferritin light chain,CCAAT/enhancer binding protein homologous protein,glucose-regulated protein 78,etc.)in vitro,suggesting the involvement of an Hv1-reactive oxygen species-glucose-regulated protein 78 axis in diabetic demyelination.We highlight the translational implications of these findings and recommend future studies employing microglia-specific Hv1 deletion models,longitudinal cognitive assessments and preclinical evaluation of pharmacological Hv1 inhibitors.
基金Supported by the National Natural Science Foundation of China,No.82300894.
文摘BACKGROUND Diabetes is associated with increased cognitive decline and dementia due to the loss of myelinated nerve fiber function,which is linked to oligodendrocyte dysfunction.The voltage-gated proton channel 1(Hv1)is important for the cellular proton extrusion machinery.However,its role in regulating diabetesinduced cognitive dysfunction is unclear.AIM To investigate the role of Hv1 in cognitive impairment induced by diabetes and its potential mechanisms,focusing on neuroinflammation,oligodendrocyte apoptosis,and axonal demyelination.METHODS A diabetes model was established by administering a high-fat diet and streptozotocin injections in mice.Hv1 knockout(KO)and wild-type mice were used to evaluate cognitive function via behavioral tests and neuroinflammation using immunofluorescence.Oligodendrocyte apoptosis was assessed with the terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay, and axonal demyelination wasanalyzed using electron microscopy.RESULTSHv1 expression was significantly increased in the corpus callosum of diabetic mice. Hv1 KO alleviated cognitiveimpairment, reduced oligodendrocyte apoptosis, and decreased the expression of inflammatory factors, includinginterleukin-1 and tumor necrosis factor-α, in diabetic mice. Electron microscopy revealed a reduction in myelinthickness and an increased g-ratio in diabetic mice, which were reversed by Hv1 KO.CONCLUSIONHv1 plays a role in diabetes-induced cognitive dysfunction by modulating neuroinflammation and myelinintegrity. Hv1 KO demonstrates therapeutic potential in mitigating diabetes-related cognitive decline andassociated complications.
文摘Voltage-gated ion channels(VGICs) are central to cellular excitation, orchestrating skeletal and cardiac muscle contractions and enabling neural signal transduction. Among these, voltage-gated potassium(Kv) channels are particularly significant in cardiac electrophysiology, especially during the repolarization phase of the cardiac action potential. In cardiac myocytes, Kv channels are integral to a multitude of sophisticated functions, including electrical conduction. Despite their importance, research on Kv channels in the context of cardiovascular diseases is limited. This review offers a comprehensive summary of the structural complexities of Kv channels, delineating the regulatory mechanisms involved in channel gating, expression, and membrane localization. Additionally, we examine the role of different Kv α-subunits in modulating Kv channels and their impact on cardiac remodeling, and assess the potential of targeting Kv channels for the development of anti-arrhythmic therapies.
基金National Essence Basic Research and Development 973 Program:the Effects of Meridian Specific Target Organ Response on Biological Basic Research(No.2012CB518503)
文摘OBJECTIVE: To examine the effect of electroacupuncture(EA) at bilateral Neiguan(PC 6) on voltage-gated Na+currents(INa) and channels(Nav) in ischemic ventricular myocytes.METHODS: EA serum was prepared from six male adult Sprague-Dawley rats that had received EA at bilateral Neiguan(PC 6). Eighteen ventricular myocytes were prepared from six SD rats using an enzymolysis approach. Myocardial ischemia was mimicked by perfusion of ischemic solution. Whole-cell patch-clamping was used to record three currents evoked from isolated cells. The first current was the control, and recorded in absence of ischemic solution current. The second was the ischemic current,and recorded after perfusion of ischemic solution for 5 min, while the EA current was last, and recorded after perfusion of EA serum for 5 min. Navkinetic curves were fitted using related formulas.RESULTS: Compared with those in controls, in the presence of ischemic solution, peak amplitudes of INasignificantly increased from ﹣40 m V to +30 m V,and half-maximal inactivation potentials of Navincreased significantly, while half-maximal activation potentials, slope factors and the recovery time from inactivation to activation of Navwere unchanged. Compared with those in the ischemic solution, in the presence of EA serum, peak ischemic current amplitudes significantly reduced from ﹣40m V to + 40 m V, and half-maximal inactivation potentials were restored, while half-maximal activation potentials, slope factors and the recovery time from inactivation to activation of Navwere unchanged.CONCLUSION: EA at bilateral Neiguan(PC 6) can reduce enhanced INavia restoration of delayed Navinactivation in ischemic ventricular myocytes.
基金the National Basic Research Development Program of China (No. 2006CB500801).
文摘Objective To examine the effect of deglycosylation on gating properties of rNav1.3. Methods rNav1.3 was expressed in Xenopus oocyte, with glycosylation inhibition by using tunicamycin. Two-electrode voltage clamp was employed to record the whole-cell sodium current and data were analyzed by Origin software. Those of glycosylated rNav1.3 were kept as control. Results Compared with glycosylated ones, the steady-state activation curve of deglycosylated rNav1.3 was positively shifted by about 10 mV, while inactivation curve was negatively shifted by about 8 mV. Conclusion Glycosylation altered the gating properties of rNav 1.3 and contributed to the functional diversity.
基金supported in part by NIH RO1Grants NS87988,DE17794,and DE22743 to R.R.J and NS89479 to S.Y.L and R.R.J
文摘Voltage-gated sodium channels （Navs） play an important role in human pain sensation. However, the expression and role of Nav subtypes in native human sensory neurons are unclear. To address this issue, we obtained human dorsal root ganglion （hDRG） tissues from healthy donors. PCR analysis of seven DRG-expressed Nav subtypes revealed that the hDRG has higher expression of Navl.7 （,-~ 50% of total Nav expression） and lower expres- sion of Navl.8 （~ 12%）, whereas the mouse DRG has higher expression of Nav 1.8 （- 45%） and lower expression of Navl.7 （- 18%）. To mimic Nav regulation in chronic pain, we treated hDRG neurons in primary cultures with paclitaxel （0.1-1 μmol/L） for 24 h. Paclitaxel increased the Navl.7 but not Navl.8 expression and also increased the transient Na＋ currents and action potential firing frequency in small-diameter （〈50 ~tm） hDRG neurons. Thus, the hDRG provides a translational model in which to study ＂human pain in a dish＂ and test new pain therapeutics.
基金supported by a grant from the National Natural Science Foundation of China,No.30972766,31170852,81001322,81172795,81173048the Specialized Research Fund for the Doctoral Program of Colleges and Universities,No.20094402110004
文摘Interleukin-6 has been shown to be involved in nerve injury and nerve regeneration, but the effects of long-term administration of high concentrations of interleukin-6 on neurons in the central nervous system is poorly understood. This study investigated the effects of 24 hour expo-sure of interleukin-6 on cortical neurons at various concentrations （0.1, 1, 5 and 10 ng/mL） and the effects of 10 ng/mL interleukin-6 exposure to cortical neurons for various durations （2, 4, 8, 24 and 48 hours） by studying voltage-gated Na＋ channels using a patch-clamp technique. Volt-age-clamp recording results demonstrated that interleukin-6 suppressed Na＋ currents through its receptor in a time- and dose-dependent manner, but did not alter voltage-dependent activation and inactivation. Current-clamp recording results were consistent with voltage-clamp recording results. Interleukin-6 reduced the action potential amplitude of cortical neurons, but did not change the action potential threshold. The regulation of voltage-gated Na＋channels in rat corti-cal neurons by interleukin-6 is time- and dose-dependent.
基金the National Natural Science Foundation of China, No.30903123, 30901329the Project of Science and Technology of Jilin Province, No.20090741, 20090185
文摘Activin A, which was first described in 1986, has been shown to maintain hippocampal neuronal survival. Activin A increases intracellular free Ca2＋ via L-type Ca2＋ channels. Our previous study showed that activin A promotes neurite growth of dorsal root ganglia in embryonic chickens and inhibits nitric oxide secretion. The present study demonstrated for the first time that activin A could maintain cerebral cortex neuronal survival in vitro for a long period, and that activin A was shown to increase voltage-gated Na＋ current （/Na） in Neuro-2a cells, which was recorded by patch clamp technique. The present study revealed a novel mechanism for activin A, as well as the influence of activin A on neurons by regulating expressions of vasoactive intestine peptide and inducible nitric oxide synthase.
文摘Voltage-gated sodium channels (VGSCs) play a fundamental role in controlling cellular excitability,and their abnormal activity is related to several pathological processes,including cardiac arrhythmias,epilepsy,neurodegenerative diseases,spasticity and chronic pain.In particular,chronic visceral pain,the central symptom of functional gastrointestinal disorders such as irritable bowel syndrome,is a serious clinical problem that affects a high percentage of the world population.In spite of intense research efforts and after the dedicated decade of pain control and research,there are not many options to treat chronic pain conditions.However,there is a wealth of evidence emerging to give hope that a more refined approach may be achievable.By using electronic databases,available data on structural and functional properties of VGSCs in chronic pain,particularly functional gastrointestinal hypersensitivity,were reviewed.We summarize the involvement and molecular bases of action of VGSCs in the pathophysiology of several organic and functionalgastrointestinal disorders.We also describe the efficacy of VGSC blockers in the treatment of these neurological diseases,and outline future developments that may extend the therapeutic use of compounds that target VGSCs.Overall,clinical and experimental data indicate that isoform-specific blockers of these channels or targeting of their modulators may provide effective and novel approaches for visceral pain therapy.
文摘Atrial fibrillation(AF)is the most common cardiac arrhythmia worldwide.The prevalence of the disease increases with age,strongly implying an age-related process underlying the pathology.At a time when people are living longer than ever before,an exponential increase in disease prevalence is predicted worldwide.Hence unraveling the underlying mechanics of the disease is paramount for the development of innovative treatment and prevention strategies.The role of voltage-gated sodium channels is fundamental in cardiac electrophysiology and may provide novel insights into the arrhythmogenesis of AF.Na_v1.5 is the predominant cardiac isoform,responsible for the action potential upstroke.Recent studies have demonstrated that Na_v1.8(an isoform predominantly expressed within the peripheral nervous system)is responsible for cellular arrhythmogenesis through the enhancement of pro-arrhythmogenic currents.Animal studies have shown a decline in Na_v1.5 leading to a diminished action potential upstroke during phase 0.Furthermore,the study of human tissue demonstrates an inverse expression of sodium channel isoforms;reduction of Na_v1.5 and increase of Na_v1.8 in both heart failure and ventricular hypertrophy.This strongly suggests that the expression of voltage-gated sodium channels play a crucial role in the development of arrhythmias in the diseased heart.Targeting aberrant sodium currents has led to novel therapeutic approaches in tackling AF and continues to be an area of emerging research.This review will explore how voltage-gated sodium channels may predispose the elderly heart to AF through the examination of laboratory and clinical based evidence.
文摘Voltage-gated sodium channels （VGSCs） are known to be involved in the initiation and progression of many malignancies, and the different subtypes of VGSCs play important roles in the metastasis cascade of many tumors. This study investigated the functional expression of Nav1.5 and its effect on invasion behavior of human breast cancer cell line MDA-MB-231. The mRNA and protein expression of Nav1.5 was detected by real time PCR, Western Blot and immunofluorescence. The effects of Nav1.5 on cell proliferation, migration and invasion were respectively assessed by MTT and Transwell. The effects of Nav1.5 on the secretion of matrix metalloproteases （MMPs） by MDA-MB-231 were analyzed by RT-PCR. The over-expressed Nav 1.5 was present on the membrane of MDA-MB-231 cells. The invasion ability in vitro and the MMP-9 mRNA expression were respectively decreased to （47.82±0.53）% and （43.97±0.64）% （P〈0.05） respectively in MDA-MB-23 t cells treated with VGSCs specific inhibitor tetrodotoxin （TTX） by blocking Navl.5 activity. It was concluded that Navl.5 functional expression potentiated the invasive behavior of human breast cancer cell line MDA-MB-231 by increasing the secretion of MMP-9.
基金supported by the National Natural Science Foundation of China(32071003,82271249,and 81873808)the 1-3-5 Project for Disciplines of Excellence of West China Hospital of Sichuan University(ZYJC21034).
文摘Hv1 is the only voltage-gated proton-selective channel in mammalian cells.It contains a conserved voltage-sensor domain,shared by a large class of voltage-gated ion channels,but lacks a pore domain.Its primary role is to extrude protons from the cytoplasm upon pH reduction and membrane depolarization.The best-known function of Hv1 is the regulation of cytosolic pH and the nicotinamide adenine dinucleotide phosphate oxidase-dependent production of reactive oxygen species.Accumulating evidence indicates that Hv1 is expressed in nervous systems,in addition to immune cells and others.Here,we summarize the molecular properties,distribution,and physiological functions of Hv1 in the peripheral and central nervous systems.We describe the recently discovered functions of Hv1 in various neurological diseases,including brain or spinal cord injury,ischemic stroke,demyelinating diseases,and pain.We also summarize the current advances in the discovery and application of Hv1-targeted small molecules in neurological diseases.Finally,we discuss the current limitations of our understanding of Hv1 and suggest future research directions.
基金supported by the National Science Foundation of China (Grant No. 81000456)the Science and Technology Department of Sichuan Province (Grant No. 2009SZ0171)
文摘Chlorogenic acid（5-caffeoylquinic acid, CGA） is a phenolic compound that is found ubiquitously in plants, fruits and vegetables and is formed via the esterification of caffeic acid and quinic acid. In addition to its notable biological functions against cardiovascular diseases, type-2 diabetes and inflammatory conditions, CGA was recently hypothesized to be an alternative for the treatment of neurological diseases such as Alzheimer＇s disease and neuropathic pain disorders. However, its mechanism of action is unclear.Voltage-gated potassium channel（Kv） is a crucial factor in the electro-physiological processes of sensory neurons. Kv has also been identified as a potential therapeutic target for inflammation and neuropathic pain disorders. In this study, we analysed the effects of CGA on the two main subtypes of Kv in trigeminal ganglion neurons, namely, the IK,Aand IK,Vchannels. Trigeminal ganglion（TRG）neurons were acutely disassociated from the rat TRG, and two different doses of CGA（0.2 and 1 mmol·L21） were applied to the cells.Whole-cell patch-clamp recordings were performed to observe alterations in the activation and inactivation properties of the IK,Aand IK,Vchannels. The results demonstrated that 0.2 mmol·L21CGA decreased the peak current density of IK,A. Both 0.2 mmol·L21and1 mmol·L21CGA also caused a significant reduction in the activation and inactivation thresholds of IK,Aand IK,V. CGA exhibited a strong effect on the activation and inactivation velocities of IK,Aand IK,V. These findings provide novel evidence explaining the biological effects of CGA, especially regarding its neurological effects.
文摘AIM： To investigate the action of genistein （GST）, a broad spectrum tyrosine kinase inhibitor, on voltagegated potassium channels in guinea pig proximal colon smooth muscle cells. METHODS： Smooth muscle cells in guinea pig proximal colon were enzymatically isolated. Nystatin-perforated whole cell patch clamp technique was used to record potassium currents including fast transient outward current （Ikto） and delayed rectifier current （Ikdr）, tWO of which were isolated pharmacologically with 10 mmol/L tetraethylammonium or 5 mmol/L 4-aminopyridine. Contamination of calcium-dependent potassium currents was minimized with no caldum and 0.2 mmol/L CdCl2 in an external solution. RESULTS： GST （10-100 μmol/L） reversibly and dosedependently reduced the peak amplitude of Ikto with an IC50 value of 22.0±6.9 μmol/L. To a lesser extent, Ikdr, was also inhibited in both peak current and sustained current. GST could not totally block the outward potassium current as a fraction of the outWard potassium current, which was insensitive to GST. GST had no effect on the steady-state activation （n =6） and inactivation kinetics （n =6） of Ikto. Sodium orthovanadate （1 retool/L）, a potent inhibitor of tyrosine phosphatase, significantly inhibited GST-induced inhibition （P〈 0.05）. CONCLUSION： GST can dose-dependently and reversibly block voltage-gated potassium channels in guinea pig proximal colon smooth muscle cells.
基金We thank Prof.Lin Chen(University of Science and Technology of China)and Dr.Juanmei Yang(Eye and ENT Hospital of Fudan University)for valuable help with cochlear microscopic anatomy.This work was supported by the National Natural Science Foundation of China(31571032,31771191.81730028)the National Basic Research Development Program of China(SQ2017YFSF080012)the Postdoctoral Science Foundation of China(2018M640407).
文摘Voltage-gated sodium channels(VGSCs)are transiently expressed in cochlear hair cells before hearing onset and play an indispensable role in shaping spontaneous activity.In this study,we showed that Na^+currents shaped the spontaneous action potentials in developing mouse inner hair cells(IHCs)by decreasing the time required for the membrane potential to reach the action-potential threshold.In immature IHCs,we identified 9 known VGSC subtypes(Navl.la-l.9ot),among which Navl.7a was the most highly expressed subtype and the main contributor to Na+currents in developing hair cells.Electrophysiological recordings of two cochlea-specific Navi.7 variants(CbmNavl.7a and CbmNavl.7b)revealed a novel loss-of-function mutation(C934R)at the extracellular linker between segments 5 and 6 of domain II.In addition,post-transcriptional modification events,such as alternative splicing and RNA editing,amended the gating properties and kinetic features of CbmNavl.7a(C934).These results provide molecular and functional characteristics of VGSCs in mammalian IHCs and their contributions to spontaneous physiological activity during cochlear maturation.
基金the National Natural Science Foundation of China(Nos.81473254,81773637,81773594,U1703111)the Fundamental Research Fund for the Central Universities(No.2017KFYXJJ151).
文摘Voltage-gated sodium(Nav)channels are critical players in the generation and propagation of action potentials by triggering membrane depolarization.Mutations in Nav channels are associated with a variety of channelopathies,which makes them relevant targets for pharmaceutical intervention.Sofar,the cryoelectron microscopic structure of the human Nav 1.2,Nav 1.4,and Nav 1.7 has been reported,which sheds light on the molecular basis of functional mechanism of Nav channels and provides a path toward structure-based drug discovery.In this review,we focus on the recent advances in the structure,molecular mechanism and modulation of Nav channels,and state updated sodium channel blockers for the treatment of pathophysiology disorders and briefly discuss where the blockers may be developed in the future.
基金This work was supported by an operaing grant and a scholarship from the Medical Research Council of Canada(MRC)and by a start-up fund from the Hospital for Sick Children Research Institute to L,Y.W.
文摘Objective. To investigate the properties of voltage-gated sodium (Na+) channels in developing auditoryneurons during early postnatal stages in the mammalian central nervous system.Methods. Using the whole-cell voltage-clamp technique, we have studied changes in the electrophysi-ological properties of Na+ channels in the principal neurons of the medial nucleus of the trapezoid body (MNTB).Results. We found that MNTB neurons already express functional Na+ channels at postnatal day 1 (P1),and that channel density begins to increase at P5 when the neurons receive synaptic innervation andreach its maximum (～3 fold) at P11 when functional hearing onsets. These changes were paralleled byan age-dependent acceleration in both inactivation and recovery from inactivation. In contrast, there wasvery little alteration in the voltage-dependence of inactivation.Conclusion. These profound changes in the properties of voltage-gated Na+ channels may increase theexcitability of MNTB neurons and enhance their phase-locking fidelity and capacity during high-frequencysynaptic transmission.
文摘Objective The purpose of our study is to observe the voltage-gated potassium channel Kvl.3 expressed on CD4＋CD28~ T cells from the peripheral blood of acute coronary syndrome （ACS） patients by the patch clamp technique. Methods Kvl.3 potassium channels expression from 17 patients with ACS and 11 healthy age-match controls was detected in single cell（CD4＋CD28null T cells and CD4＋CD28＋T cells） by fluorescence mieroscopy and patch clamp. Results The percentage of CD4＋CD28mullT cells was higher in the ACS patients [（6.97±2.05）%] than that in the controls [（1.38±0.84）%, P〈0.05]. The concentration of hsCRP was directly correlated with the number of the CD4~CD28nul~ T cells in the ACS patients （r=0.52, P〈0,05）. The conductance （6.89±1.17ns vs 3.36±0.66ns）, dens （1.95±0.80 μm2 vs 1.13±0.57 μm2） and numbers （574.5±97.6 n/cell vs. 280.3±55.3 n/cell） of the Kv1.3 channels on the CIM＋CD28null T cells were significantly higher than those on the CD4＋CD28＋ T cells （all P〈0.01） in ACS patients, but were similar on CD4＋CD28＋T betweenACS patients and controls. Conclusion The CD4＋CD28nullT cells and the numbers of Kvl.3 channels on the CD4＋CD28nullT cells from patients with ACS are significantly upregulated and might contribute to the pathogenesis of ACS （d Geriatr Cardio12010; 7：40-46）.
基金the Foundation of Supported by National Natural Science Foundation of China(32070392 and 32070393)the Second Tibetan Plateau Scientific Expedition and Research(STEP)program(2019QZKK0502-0303).
文摘Saldigones A-C(1,3,4),three new isoprenylated flavonoids with diverse flavanone,pterocarpan,and isoflavanone architec-tures,were characterized from the roots of Salvia digitaloides,together with a known isoprenylated flavanone(2).Notably,it’s the first report of isoprenylated flavonoids from Salvia species.The structures of these isolates were elucidated by extensive spectroscopic analysis.All of the compounds were evaluated for their activities on Cav3.1 low voltage-gated Ca^(2+)channel(LVGCC),of which 2 strongly and dose-dependently inhibited Cav3.1 peak current.
文摘Introduction: Antibodies to voltage-gated potassium channels have been implicated in causing a host of peripheral and central nervous system disorders. However, the presence of these antibodies has not been previously associated with motor neuropathy. We describe the first case of acquired motor neuron disease associated with voltage-gated potas-sium channel antibodies. Case Report: The patient is an 81-year-old female who developed signs and symptoms of an idiopathic motor neuron disease. The patient was found to have increased antibodies to voltage-gated potassium chan-nels in the absence of a known metastatic or autoimmune process. Magnetic resonance imaging of the cervical spine demonstrated increased signal in the anterior horn regions of the cervical and upper thoracic spinal cord on T2-weighted imaging. The patient’s disease progression was refractory to both intravenous immunoglobulin and ster-oid therapy. Conclusion: Voltage-gated potassium channels may be causal or simply associated with motor neuron disease;this relationship needs to be elucidated. Testing for these antibodies may be warranted in cases of idiopathic rapidly progressing motor neuron disease.
