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Do age-associated changes of voltage-gated sodium channel isoforms expressed in the mammalian heart predispose the elderly to atrial fibrillation?

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World Journal of Cardiology 2020年第4期12卷 123-135页

作者： Emmanuel Isaac Stephanie M Cooper Sandra A Jones Mahmoud Loubani Department of Cardiothoracic Surgery Hull University Teaching HospitalsCottingham HU165JQUnited Kingdom Department of Biomedical Sciences University of HullHull HU67RXUnited Kingdom

Atrial fibrillation(AF)is the most common cardiac arrhythmia *** prevalence of the disease increases with age,strongly implying an age-related process underlying the *** a time when people are living longer than ever before,an exponential increase in disease prevalence is predicted *** unraveling the underlying mechanics of the disease is paramount for the development of innovative treatment and prevention *** role of voltage-gated sodium channels is fundamental in cardiac electrophysiology and may provide novel insights into the arrhythmogenesis of ***_v1.5 is the predominant cardiac isoform,responsible for the action potential *** 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 *** studies have shown a decline in Na_v1.5 leading to a diminished action potential upstroke during phase ***,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 *** strongly suggests that the expression of voltage-gated sodium channels play a crucial role in the development of arrhythmias in the diseased *** aberrant sodium currents has led to novel therapeutic approaches in tackling AF and continues to be an area of emerging *** review will explore how voltage-gated sodium channels may predispose the elderly heart to AF through the examination of laboratory and clinical based evidence.

关键词： voltage-gated Sodium channels Ageing Atrial fibrillation Nav1.5 Nav1.8 Late sodium current Cardiac electrophysiology

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Motor Neuron Disease Associated with voltage-gated Potassium Channel Antibodies

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Neuroscience & Medicine 2011年第2期2卷 68-70页

作者： Eric M. Thompson Robert A. E gan 不详

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.

关键词： voltage-gated Potassium Channels Motor Neuron Disease Antibody Central Nervous System Disorders

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Molecular Docking Studies on Anticonvulsant Enaminones Inhibiting voltage-gated Sodium Channels

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Open Journal of Physical Chemistry 2019年第4期9卷 241-257页

作者： Yayin Fang Jamiya Kirkland Isis J. Amaye Patrice Jackson-Ayotunde Matthew George Jr. Department of Biochemistry and Molecular Biology College of Medicine Howard University Washington DC USA Department of Pharmaceutical Sciences School of Pharmacy and Health Professions University of Maryland Eastern Shore Princess Anne MD USA

Epilepsy is described as the most common chronic brain disorder. A typical symptom of epilepsy results in uncontrolled convulsions caused by temporary excessive neuronal discharges. Although several new anticon-vulsants have been introduced, some types of seizures have still not been adequately controlled with these new and current therapies. There is an urgent need to develop new anticonvulsant drugs to control the many different types of seizures. Many studies have shown that the epilepsies involve more than one mechanism and therefore may be responsible for the various types of observed seizures. Recently reported studies have shown that a group of newly synthesized 6 Hz active anticonvulsant fluorinated N-benzamide enaminones exhibited selective inhibitions of voltage-gated sodium (Nav) channels. Nav channels are responsible for the initial inward currents during the depolarization phases of the action potential in excitable cells. The activation and opening of Nav channels result in the initial phases of action potentials. We hypothesize that there is an essential pharmacophore model for the interactions between these enaminones and the active sites of Nav channels. The research reported here is focused on molecular docking studies of the interactions that occur between the fluorinated N-benzamide enaminones and the Nav channels. These studies may open an avenue for designing anticonvulsant drugs by inhibiting Nav channels.

关键词： Anticonvulsant Enaminones voltage-gated Sodium Channels Structure-Based Drug Design Molecular Docking 3D QSAR

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Dopamine D2 Receptor-Mediated Modulation of Rat Retinal Ganglion Cell Excitability

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Neuroscience Bulletin 2020年第3期36卷 230-242页

作者： Ning Yin Yu-Long Yang Shuo Cheng Hong-Ning Wang Xin Hu Yanying Miao Fang Li Zhongfeng Wang Department of Neurology State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain ScienceInstitutes of Brain ScienceZhongshan HospitalFudan UniversityShanghai 200032China

Ganglion cells(RGCs) are the sole output neurons of the retinal circuity. Here, we investigated whether and how dopamine D2 receptors modulate the excitability of dissociated rat RGCs. Application of the selective D2 receptor agonist quinpirole inhibited outward K^+ currents, which were mainly mediated by glybenclamide-and 4-aminopyridine-sensitive channels, but not the tetraethylammonium-sensitive channel. In addition,quinpirole selectively enhanced Nav1.6 voltage-gated Na^+ currents. The intracellular c AMP/protein kinase A,Ca^2+/calmodulin-dependent protein kinase Ⅱ, and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathways were responsible for the effects of quinpirole on K^+ and Na^+ currents, while phospholipase C/protein kinase C signaling was not involved. Under current-clamp conditions, the number of action potentials evoked by positive current injection was increased by quinpirole. Our results suggest that D2 receptor activation increases RGC excitability by suppressing outward K+currents and enhancing Nav1.6 currents, which may affect retinal visual information processing.

关键词： Retinal ganglion cell Dopamine D2 receptor Outward K^+current Nav1.6 voltage-gated Na^+current Excitability

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Cellular and Molecular Mechanisms Underlying Arterial Baroreceptor Remodeling in Cardiovascular Diseases and Diabetes

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Neuroscience Bulletin 2019年第1期35卷 98-112页

作者： Huiyin Tu Dongze Zhang Yu-Long Li Department of Emergency Medicine University of Nebraska Medical CenterOmahaNE 68198USA

Clinical trials and animal experimental studies have demonstrated an association of arterial baroreflex impairment with the prognosis and mortality of cardiovascular diseases and diabetes. As a primary part of the arterial baroreflex arc, the pressure sensitivity of arterial baroreceptors is blunted and involved in arterial baroreflex dysfunction in cardiovascular diseases and *** in the arterial vascular walls, mechanosensitive ion channels, and voltage-gated ion channels contribute to the attenuation of arterial baroreceptor sensitivity. Some endogenous substances(such as angiotensin II and superoxide anion) can modulate these morphological and functional alterations through intracellular signaling pathways in impaired arterial baroreceptors. Arterial baroreceptors can be considered as a potential therapeutic target to improve the prognosis of patients with cardiovascular diseases and diabetes.

关键词： Cardiovascular disease Diabetes Baroreflex Baroreceptor Vascular wall Mechanosensitive ion channels voltage-gated ion channels Angiotensin Ⅱ Superoxide Nuclear factor-kappa B

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Prediction of post-progression survival in patientswith advanced hepatocellular carcinoma treated with sorafenib by using time-dependent changes inclinical characteristics

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Hepatoma Research 2018年第3期4卷 1-8页

作者： Yoshiyuki Wada Yuko Takami Hajime Matsushima Masaki Tateishi Tomoki Ryu Munehiro Yoshitomi Hideki Saitsu Department of Hepato-Biliary-Pancreatic Surgery Clinical Research InstituteNational Hospital Organization Kyushu Medical CenterFukuoka 810-8563Japan

Aim: Sorafenib has been shown to improve time to tumor progression (TTP) and overall survival (OS) in patients with hepatocellular carcinoma (HCC);however, post-progression survival (PPS) has not been well characterized in these patients. This study aimed to evaluate the predictors of PPS by using time-dependent and dynamic changes in radiologic progression patterns, liver function, and performance status (PS) in patients with advanced HCC receiving sorafenib treatment. Methods: We retrospectively analyzed the clinical characteristics of 128 advanced HCC patients with Child-Pugh scores ≤ 7 at the initiation of sorafenib treatment. Results: The median TTP, OS, and PPS were 3.8, 15.6, and 9.9 months, respectively. At the time of confirmation of radiologic progressive disease (PD), a total of 46 (35.6%) patients showed impairments in their PS of ≥ +1 points over time. For the Child-Pugh score, 27 (21.1%) and 26 (10.9%) patients exhibited an impairment of ≥ +1 and ≥ +2 points, respectively. Multivariate analysis identified the following independent predictors of PPS: impairment in the PS score of ≥+1 point [hazard ratio (HR) 1.81, 95% confidence interval (CI) 1.16-2.82], impairment in the Child-Pugh score of ≥ +2 points (HR 3.70, 95% CI 1.68-8.15), radiologic pattern of progression (target lesion growth and emergence of a new lesion) (HR 2.91, 95% CI 1.79-2.91), a TTP < 4 months(HR 1.87, 95% CI 1.21-2.91), second-line treatment after radiologic confirmation of PD (HR 0.16, 95% CI 0.08-0.32), and continuous sorafenib treatment after radiologic confirmation of PD (HR 1.76, 95% CI 1.06-3.00). Conclusion: PPS in patients with advanced HCC can be characterized by using time-dependent dynamic changes in clinical parameters.

关键词： Contactin-associated protein-2 Isaac neuromuscular hyperexcitability neuromyotonia voltage-gated potassium channel

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Steroids and plasma exchange in Isaacs' syndromewith anti-Caspr2 antibodies

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Neuroimmunology and Neuroinflammation 2018年第3期5卷 5-9页

作者： Daniele Orsucci Gianfranco Cafforio Gianluca Moscato Alessandro Napolitano Marco Margelli Monica Mazzoni Unit of Immunohematology and Transfusional Medicine San Luca HospitalLucca55100Italy

Isaacs' syndrome is a disease characterized by nerve hyperexcitability. The patients are commonly treated with symptomatic therapies and immunomodulatory approaches, but no clinical trials are available to date. Here, we report the case of an anti-Caspr2-positive patient, presenting with continuous muscle twitches and diffuse muscle pain. He experienced a nearly complete clinical response to intravenous high-dose steroids combined with plasma exchange, sustained for at least 1 year. Our experience suggests that methylprednisolone 1000 mg/day × 5 days and consecutive tapering followed by plasma exchange may be efficient and well tolerated in patient with Isaacs' syndrome due to anti-Caspr2 antibodies.

关键词： Contactin-associated protein-2 Isaac neuromuscular hyperexcitability neuromyotonia voltage-gated potassium channel

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KCN基因对小鼠脂代谢的影响及其机制初探

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首都医科大学学报 2017年第2期38卷 161-166页

作者：刘敬怡卢晶杨金奎首都医科大学附属北京同仁医院内分泌科北京100730 糖尿病防治研究北京市重点实验室北京100730

目的研究钾离子电压门控通道(potassium voltage-gated channel,KCN)基因对小鼠脂代谢的影响及其相关信号通路,为治疗糖尿病的脂肪异常提供新的治疗靶点。方法采用KCN基因敲除的小鼠模型及对照C57BL/6野生小鼠动物模型,检测三酰甘油、... 详细信息

目的研究钾离子电压门控通道(potassium voltage-gated channel,KCN)基因对小鼠脂代谢的影响及其相关信号通路,为治疗糖尿病的脂肪异常提供新的治疗靶点。方法采用KCN基因敲除的小鼠模型及对照C57BL/6野生小鼠动物模型,检测三酰甘油、胆固醇、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇等脂代谢相关指标。HE染色观察小鼠肝脏组织脂肪变。Western blotting法测定小鼠肝脏组织腺苷酸激活蛋白激酶[adenosine 5'-monophosphate(AMP)-activated protein kinase,AMPK]通路相关蛋白的表达。结果 KCN基因敲除小鼠较野生型对照小鼠血清中三酰甘油、总胆固醇和低密度脂蛋白胆固醇浓度均明显增高,差异有统计学意义(P<0.05)高密度脂蛋白明显降低,肝脏HE染色显示基因敲除小鼠肝脏内脂滴的数目和体积均与野生型有明显差异,Western blotting结果显示KCN基因敲除小鼠肝脏组织中磷酸化蛋白激酶B(phosphate-protein kinase B,Phos-AKT)、磷酸化乙酰辅酶A羧化酶(phosphate-acetyl CoA carboxylase,Phos-ACC)、phos-AMPK浓度均较正常对照组小鼠表达量降低,phosACCα水平较正常对照组小鼠明显增高差异有统计学意义(P<0.05)。结论 KCN基因对小鼠血脂代谢有保护作用,其作用机制与AMPK的脂肪酸氧化有关。

关键词：钾离子电压门控通道(potassium voltage-gated channel,KCN) 脂代谢 AMPK通络

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Interactions of variants in the CACNA1C gene with smoking on blood pressure responses to potassium intervention:the GenSalt Study

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中国循环杂志 2018年第S1期33卷 113-113页

作者： Can Cai Xinyuan Gong Jianfeng Huang Xiangfeng Lu Jichun Chen Jie Cao Jianxin Li Hongfan Li Shufeng Chen Dongfeng Gu State Key Laboratory of Cardiovascular Disease National Center for Cardiovascular DiseasesFuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina

Objective Calcium voltage-gated Channel Subunit Alpha1 C(CACNA1C)gene encodes an alpha-1 subunit of a voltage-dependent calcium *** subunit forms the pore through which calcium ions pass into the cell and plays an important role in regulating blood *** habit has been proven become the risk factor of *** study aimed to investigate the interaction of variants in CACNA1C gene with smoke in blood pressure(BP)responses to dietary sodium and potassium intervention.

关键词： Calcium voltage-gated Channel Subunit Alpha1 C(CACNA1C) blood pressure Smoking

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