更新于：2024-09-19

Kir4.1

更新于：2024-09-19

基本信息

别名

ATP-dependent inwardly rectifying potassium channel Kir4.1、ATP-sensitive inward rectifier potassium channel 10、Inward rectifier K(+) channel Kir1.2

+ [6]

简介

May be responsible for potassium buffering action of glial cells in the brain. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by extracellular barium and cesium (By similarity). In the kidney, together with KCNJ16, mediates basolateral K(+) recycling in distal tubules; this process is critical for Na(+) reabsorption at the tubules.

关联

项与 Kir4.1 相关的药物

VU0134992

靶点

Kir4.1

作用机制

Kir4.1 抑制剂

在研机构

Vanderbilt University

原研机构

Vanderbilt University

在研适应症

高血压

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

VU6036720

靶点

Kir4.1 x Kir5.1

作用机制

Kir4.1 抑制剂 [+1]

在研机构

Vanderbilt University

原研机构

Vanderbilt University

在研适应症

水肿 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 Kir4.1 相关的临床结果

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100 项与 Kir4.1 相关的转化医学

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0 项与 Kir4.1 相关的专利（医药）

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800

项与 Kir4.1 相关的文献（医药）

2024-12-01·Cellular and Molecular Neurobiology

Genetic Discrimination of Grade 3 and Grade 4 Gliomas by Artificial Neural Network

Article

作者: Savelieva, Olga E ; Mekler, Aleksei A ; Schwartz, Dmitry R

Gliomas, including anaplastic gliomas (AG; grade 3) and glioblastomas (GBM; grade 4), are malignant brain tumors associated with poor prognosis and low survival rates. Current classification systems based on histopathology have limitations due to intratumoral heterogeneity. The treatment and prognosis are distinctly different between grade 3 and grade 4 gliomas patients. Therefore, there is a need for molecular markers to differentiate these tumors accurately. In this study, we aimed to identify a gene expression signature using an artificial neural network (ANN) in application to microarray and serial analysis of gene expression (SAGE) data for grade 3 (AG) and grade 4 (GBM) gliomas discrimination. We acquired gene expression data from publicly available datasets on glial tumors of grades 3 and 4-a total of 93 grade 3 gliomas and 224 grade 4 gliomas. To select genes for classification, we implemented an artificial neural network-based method using a combination of self-organized maps (SOM) and perceptron. In general, we implemented a multi-stage procedure that involved multiple runs of a genetic algorithm to identify genes that provided optimal clusterization on the SOM. We performed this procedure multiple times, resulting in different sets of genes each time. Eventually, we selected several genes that appeared most frequently in the reduced sets and performed classification using them. Our analysis identified a set of seven genes (BCAS4, GLUD2, KCNJ10, KCND2, AKR7A2, FOLR1, and KIAA0319). The classification accuracy using this gene set was 87.5%. These findings suggest the potential of this gene set as a molecular marker for distinguishing grade 3 (AG) from grade 4 (GBM) gliomas.

2024-09-01·Experimental Neurology

Activity-dependent extracellular potassium changes in unmyelinated versus myelinated areas in olfactory regions of the isolated female guinea-pig brain

Article

作者: Uva, Laura ; de Curtis, Marco ; Bruno, Gaia

The potassium released in the extracellular space during neuronal activity is rapidly removed by glia and neurons to maintain tissue homeostasis. Oligodendrocyte-derived myelin axonal coating contributes to potassium buffering and is therefore crucial to control brain excitability. We studied activity-dependent extracellular potassium ([K⁺]_o) changes in the piriform cortex (PC), a region that features highly segregated bundles of myelinated and unmyelinated fibers. Four-aminopyridine (4AP; 50 μM) treatment or patterned high-frequency stimulations (hfST) were utilized to generate [K⁺]_o changes measured with potassium-sensitive electrodes in the myelinated lateral olfactory tract (LOT), in the unmyelinated PC layer I and in the myelinated deep PC layers in the ex vivo isolated guinea-pig brain. Seizure-like events induced by 4AP are initiated by the abrupt [K⁺]_o rise in the layer I formed by unmyelinated fibers (Uva et al., 2017). Larger [K⁺]_o shifts occurred in unmyelinated layers compared to the myelinated LOT. LOT hfST that mimicks pre-seizure discharges also generated higher [K⁺]_o changes in unmyelinated PC layer I than in LOT and deep PC layers. The treatment with the Kir4.1 potassium channel blocker BaCl₂ (100 μM) enhanced the [K⁺]_o changes generated by hfST in myelinated structures. Our data show that activity-dependent [K⁺]_o changes are intrinsically different in myelinated vs unmyelinated cortical regions. The larger [K⁺]_o shifts generated in unmyelinated structures may represent a vehicle for seizure generation.

2024-09-01·American Journal of Physiology-Renal Physiology

Deletion of KS-WNK1 promotes NCC activation by increasing WNK1/4 abundance

Article

作者: Al-Qusairi, Lama ; Ferdaus, Mohammed Z. ; Delpire, Eric ; Welling, Paul A. ; Koumangoye, Rainelli B. ; Terker, Andrew S.

In this paper, we show that KS-WNK1 is a critical component of the distal convoluted tubule (DCT) K+ switch pathway. Its deletion results in an inability of the DCT to sense changes in plasma potassium. Absence of KS-WNK1 leads to abnormally high levels of WNK4 and L-WNK1 in the DCT, resulting in increased Na-Cl phosphorylation and function. Our data are consistent with KS-WNK1 targeting WNK4 and L-WNK1 to degradation.

项与 Kir4.1 相关的新闻（医药）

2024-02-19

·生物探索

Nat Chem Biol | 高召兵/郑月明/郭江涛揭示钾通道Kir4.1是具潜力的快速抗抑郁药物靶点

引言重度抑郁症是一种普遍而严重的精神疾病，需要开发新的快速抗抑郁药。基因抑制小鼠侧缰星形细胞内整流钾通道4.1 (Kir4.1)可改善抑郁样表型。然而，Kir4.1仍然是治疗抑郁症的一个难以捉摸的药物靶点。2024年2月14日，中国科学院上海药物研究所高召兵、郑月明及浙江大学郭江涛共同通讯在Nature Chemical Biology (IF 14.8)在线发表题为“Pharmacological inhibition of Kir4.1 evokes rapid-onset antidepressant responses”的研究论文，该研究通过高通量筛选发现了一系列Kir4.1抑制剂，Lys05是迄今为止最有效的一种，它有效地抑制了天然的Kir4.1通道，同时对快速起效的抗抑郁药物的既定目标显示出高选择性。冷冻电镜结构结合电生理表征显示Lys05直接结合在Kir4.1的中心腔中。值得注意的是，单剂量的Lys05逆转了kir4.1驱动的抑郁样表型，并在多个典型抑郁症啮齿动物模型中发挥了快速起效(早在1小时)的抗抑郁作用，其疗效与(S)-氯胺酮相当。总的来说，该研究提供了一个概念证明，Kir4.1是一个有希望的快速起效抗抑郁药物的目标。重度抑郁症是最常见和最严重的精神疾病之一，影响全世界约16%的人口，并造成沉重的社会经济负担。传统的药物治疗需要数周或数月才能产生治疗效果，而且对难治性抑郁症患者的疗效很差。最近，谷氨酸N-甲基-D-天冬氨酸(NMDA)受体拮抗剂(S)-氯胺酮被批准用于治疗抑郁症，具有快速起效的特点，这为探索快速起效的药物干预提供了新的思路。然而，安全风险和滥用责任与它的应用有关。迫切需要开发安全有效、起效快的抗抑郁药和新的作用机制。由Kcnj10编码的内纠偏钾通道4.1 (Kir4.1)仅在胶质细胞(星形胶质细胞，少突胶质细胞等)在中枢神经系统。作为星形胶质细胞Kir通道的主要组成部分，Kir4.1主要负责维持星形胶质细胞特有的高K+电导和建立静息膜电位(RMP)。Kir4.1还通过一个被称为“K+空间缓冲”的过程在控制神经元兴奋性方面发挥重要作用，其中Kir4.1摄取局部释放的[K+]o，然后通过电偶联星形细胞网络重新分配K+。星形细胞Kir4.1通道功能障碍，破坏细胞外K+稳态，与一系列神经系统疾病有关，如癫痫、肌萎缩性侧索硬化症和亨廷顿病。此外，依赖于胶质细胞类型和脑区域，与Kir5.1的同源和异四聚体组装相关的复杂表达模式进一步使其生理和病理作用多样化。Lys05作为相对特异性Kir4.1通道抑制剂的鉴定（Credit: Nature Chemical Biology）最近，Kir4.1在侧链(LHb)的上调表达介导的过量K+摄取与抑郁症有关。侧链是大脑的抗奖赏中枢。细胞外K+水平的降低，从而增强了神经元的破裂。病毒将Kir4.1传递到LHb星形胶质细胞足以诱导抑郁样行为。相比之下，敲低Kir4.1蛋白或表达LHb内的显性负性通道可以改善神经元爆发放电和抑郁样表型，揭示了Kir4.1在抑郁症中的潜在治疗价值。此外，LHb神经回路也被发现参与氯胺酮的作用机制，这意味着Kir4.1靶向治疗具有快速起效的潜力。此外，现有的抗抑郁药如选择性血清素再摄取抑制剂和三环抗抑郁药在临床治疗剂量下具有Kir4.1抑制活性，表明Kir4.1通道抑制可能有助于当前的治疗。该研究通过高通量筛选引入了Lys05(1)作为Kir4.1偏好抑制剂，并通过体外和细胞内药理表征验证了其作用。冷冻电镜(cryo-EM)鉴定了Kir4.1与Lys05复合物的结构，在分子水平上提供了Lys05靶向结合的结构证据。研究发现单剂量的Lys05在给药1小时后产生快速起效的抗抑郁作用，不仅对kir4.1驱动的抑郁样表型，而且对各种抑郁动物模型，包括新奇性抑制喂养(NSF)试验、皮质酮诱导的抑郁(CORT)模型和嗅球切除(OBX)模型。因此，广谱抗抑郁反应和Lys05的高靶点特异性支持Kir4.1是开发快速起效抗抑郁药的有希望的靶点。原文链接https://www-nature-com.libproxy1.nus.edu.sg/articles/s41589-024-01555-y责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Science最新发布：全世界最前沿的125个科学问题热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文Nature | 癌症与神经系统的致命舞蹈

临床结果

2023-11-07

·BioSpace

Cerevance Announces Presentation at the SFN Neuroscience 2023 Annual Meeting

BOSTON, Nov. 07, 2023 (GLOBE NEWSWIRE) -- Cerevance, a company focused on developing novel precision therapeutics for central nervous system (CNS) diseases, today announced plans to present a poster presentation at the Neuroscience 2023 Annual Meeting presented by the Society for Neuroscience, taking place in Washington, D.C., November 11 – 15th, 2023. Presentation details Title: NETSseq platform identifies the astrocyte specific potassium channel KCNJ10 (kir4.1) as a target for the potential treatment of neurodegenerative diseases Overview: Gene expression relevant to human disease pathology can be observed using Cerevance’s proprietary NETSseq platform. Data from this approach demonstrated that KCNJ10 is expressed in astrocytes from post-mortem brain tissue of Alzheimer’s and Parkinson’s disease donors and is increased in disease. Given that KCNJ10 is a central hub of many pathways significantly impacted by CNS diseases, including glutamate uptake, targeting this gene may present a novel approach to preventing neuronal hyperexcitability in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Presenters: Clare Bender, Jenna Harvey Session and Date and Time: Potassium Channels; November 15th, 8am – 12pm ET Poster Number: C58 About Cerevance Cerevance is focused on the development of precision treatments for central nervous system (CNS) disorders, prioritizing chronic neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis (ALS). Utilizing a large and growing collection of over 14,000 human brain tissue samples, Cerevance is generating an unprecedented level of expression and epigenetic data thereby enabling the company to identify the most promising targets for the next generation of treatments for CNS disorders. The company utilizes its proprietary Nuclear Enriched Transcript Sort sequencing (NETSseq) platform and advanced machine learning techniques to uncover the gene expression profiles of select cell types to identify novel targets that are uniquely expressed in relevant circuits affected by diseases or are altered in disease states. With the information obtained from its research, combined with the expertise of its team of scientists and drug developers, Cerevance is advancing multiple therapeutics that selectively modulate the discovered targets. These treatments are progressing through clinical development, with CVN424, CVN766, and CVN293 being the furthest along in the pipeline. CVN424 is a first-in-class non-dopamine therapy that shows promise in improving both motor and non-motor symptoms of Parkinson's disease and may also have disease-delaying effects. CVN766 is a potent antagonist of the orexin 1 receptor with high selectivity over the orexin 2 receptor which may benefit a variety of psychiatric conditions including schizophrenia, anxiety/panic, binge eating/obesity, substance use disorder, and Prader-Willi Syndrome. CVN293 is a novel blocker of potassium efflux in glia, regulating the inflammasome in individuals living with ALS and Alzheimer's disease. By leveraging its extensive collection of brain tissue samples, employing advanced technologies, and generating actionable data, Cerevance aims to transform the lives of patients affected by CNS diseases. Contacts Cerevance: Johnna Simoes, ir@cerevance.com Media: Andrew Mielach, amielach@lifescicomms.com, +1-646-876-5868

2023-09-28

·生物探索

快速抗抑郁机制

氯胺酮被认为通过抑制GluN2B-N-甲基-D-天冬氨酸(NMDA)受体(NMDARs)诱导快速抗抑郁反应，这为开发更好的抗抑郁药物提供了一个有希望的机会。然而，不良副作用限制了氯胺酮的广泛应用，GluN2B抑制剂尚未获批临床使用。目前尚不清楚氯胺酮是否仅通过GluN2B依赖机制起作用。2023年9月14日，中国科学院上海有机化学研究所陈椰林及耿泱共同通讯在Nature Neuroscience（IF=25）在线发表题为“GluN2A mediates ketamine-induced rapid antidepressant-like responses”的研究论文，该研究表明在成年小鼠大脑中，一个主要的NMDAR亚基GluN2A的缺失引发了强大的抗抑郁样反应，但对模仿氯胺酮的拟精神作用的行为影响有限。研究发现，广泛的NMDAR通道阻滞剂，如氯胺酮和MK-801(二唑西平)的抗抑郁样行为效应是通过抑制GluN2A介导的，而不是通过抑制GluN2B介导的。此外，氯胺酮或MK-801治疗通过GluN2A迅速增加海马主要神经元的内在兴奋性，而不是GluN2B。总之，这些发现表明GluN2A介导氯胺酮引发的快速抗抑郁样反应。抑郁症影响着全球约10%的人口，是导致残疾和自杀的主要原因。目前，最广泛使用的抗抑郁药是选择性血清素/去甲肾上腺素再摄取抑制剂(SSRI/SNRIs)。然而，这些药物有几个警告：反应延迟，对大约30%的患者无效(治疗耐药)，不能降低自杀风险。艾氯胺酮(Spravato)是FDA批准的第一种速效抗抑郁药，是治疗难治性患者的有效选择。然而，用艾氯胺酮或外消旋氯胺酮治疗也有类似精神的副作用和成瘾的风险，这阻碍了其更广泛的应用。有必要阐明氯胺酮的潜在机制，以指导开发更安全的速效抗抑郁药。氯胺酮被认为是通过抑制NMDARs作为通道阻滞剂来引发其抗抑郁和拟精神病作用。与此一致的是，用其他NMDAR拮抗剂治疗可以减轻动物和人类的抑郁样行为。MK-801是另一种NMDAR通道阻滞剂，可诱导短暂、快速的抗抑郁反应。自杀受害者的NMDAR水平可能发生改变，编码NMDAR亚基的基因多态性与情绪障碍的风险有关，这表明NMDAR功能障碍可能与抑郁症有关。NMDAR亚型表现出不同的表达模式和电生理特性，这可能对氯胺酮的抗抑郁作用和副作用有不同的影响。特别是，GluN2B已被认为是氯胺酮抗抑郁反应的直接靶点之一。GluN2B广泛表达于γ-氨基丁酸(GABA)能中间神经元和谷氨酸能主神经元。在任何一种类型的神经元中抑制GluN2B似乎都足以引起抗抑郁作用。然而，到目前为止，还没有GluN2B选择性抑制剂被批准用于临床。在成年小鼠大脑中去除GluN2A会诱导抗抑郁样行为，但不会诱导焦虑或过度运动行为（图源自Nature Neuroscience ）NMDARs下游的几种分子，包括mTOR（哺乳动物雷帕霉素靶点）、BDNF（脑源性神经营养因子）、GSK3 β（糖原合酶激酶-3 β）、内向整流钾通道Kir4.1和eIF4Es已被认为参与了氯胺酮诱导的抗抑郁活性。然而，氯胺酮抗抑郁疗效的非NMDAR机制也被提出。遗憾的是，这些发现都没有导致成功开发出更好的快速抗抑郁药，并被批准用于临床实践。因此，寻找氯胺酮抗抑郁作用的其他机制变得越来越有必要，以指导更好的抗抑郁药的开发。GluN2A是另一种主要的NMDAR亚型，在成人大脑中广泛表达。然而，缺乏针对啮齿动物GluN2A的选择性抑制剂阻碍了GluN2A在包括抑郁症在内的脑部疾病中的作用的研究。值得注意的是，GluN2A - / -小鼠对炎症诱导的抑郁样行为具有弹性，并且在强迫游泳测试(FST)和悬尾测试(TST)中表现出减少的抑郁样行为，尽管这些小鼠在开阔场测试(OFT)中也表现出过度运动。很难解释他们在习得性无助(LH)模型中减少的不动性是否真正反映了逃跑动机的增强，还是仅仅是活动增加的结果。在该研究中，作者发现成年诱导GluN2A - / -小鼠表现出抑郁样行为减少而运动活动不增加，并且GluN2A是氯胺酮/MK-801诱导的快速抗抑郁作用所必需的，而不是过度运动。有趣的是，与GluN2B不同，GluN2A在兴奋性神经元中的活性，而不是抑制性神经元中的活性，似乎对调节这些行为至关重要。作者发现从海马体中去除GluN2A足以诱导抗抑郁样行为。此外，GluN2A抑制与CA1主神经元内在兴奋性升高有关，而GluN2B选择性抑制对改变神经元兴奋性无效。综上所述，这些累积结果表明，抑制GluN2A通过与氯胺酮/ MK-801共享的机制导致抗抑郁药样行为，但与GluN2B抑制明显不同。该论文的共同第一作者为博士生苏桐慧、卢毅，以及技术员付朝颖，陈椰林研究员和耿泱副研究员为本文共同通讯作者。该研究工作得到了来自中国科学院和上海市科委等项目的资助。文章来源“iNature”责编|文竞择校对|文竞择End往期精选围观历史性突破！不需卵子和精子就可以合成人类胚胎热文富豪用儿子血浆“回春”科学吗？Science：血液牛磺酸缺乏驱动衰老热文世界首例！35岁的她，通过机器人操刀移植的子宫，成功诞下宝宝热文为了避免心脏骤停，53岁的他成为“第一个”植入开创性除颤器的心脏病患者热文首次披露！175家生物制药公司的薪资数据：薪资中位数达20万美元点击“阅读原文”，了解更多~

临床结果临床研究