Kir5.1 x Kir4.1

更新于：2025-05-07

基本信息

关联

项与 Kir5.1 x Kir4.1 相关的药物

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 Kir5.1 x Kir4.1 相关的临床结果

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100 项与 Kir5.1 x Kir4.1 相关的转化医学

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0 项与 Kir5.1 x Kir4.1 相关的专利（医药）

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117

项与 Kir5.1 x Kir4.1 相关的文献（医药）

2025-05-01·Pflügers Archiv - European Journal of Physiology

Intracellular pH regulates the strength of the intrinsic inward rectification of Kir4.1/Kir5.1 channels

Article

作者: Ferrer, Tania ; Delgado-Ramírez, Mayra ; Sánchez-Chapula, José A ; Aréchiga-Figueroa, Iván A ; Rodríguez-Menchaca, Aldo A ; Moreno-Galindo, Eloy G ; Marmolejo-Murillo, Leticia G ; Zamora-Cárdenas, Rodrigo ; Navarro-Polanco, Ricardo A

Kir4.1/Kir5.1 channels play a crucial role in important physiological functions, notably in the kidneys and brain. A hallmark of these channels is the coexistence of two mechanisms of inward rectification: the classical "extrinsic" inward rectification induced by polyamines and Mg²⁺ blocking the pore, and a novel "intrinsic" voltage-dependent mechanism driven by K⁺ flux. Previous studies have shown that Kir4.1/Kir5.1 channels are modulated by the intracellular pH in the physiological range. Here, we investigated the influence of the intracellular pH on the extent of the intrinsic inward rectification of Kir4.1/Kir5.1 channels expressed in HEK-293 cells and recorded using the inside-out configuration of the patch-clamp technique. We found that mutations that are known to modulate the pH sensitivity of Kir4.1/Kir5.1 channels attenuated inward rectification. The combination of these mutations in the triple mutant channel Kir4.1(K67M)/Kir5.1(N161E-R230E) virtually abolished inward rectification at pH 7.4; however, this property was re-established at acidic pH values. Consistently, the strong inward rectification of wild-type Kir4.1/Kir5.1 channels was reduced by intracellular alkalinization and further enhanced by acidification. Altogether, these experiments indicate that the intracellular pH strongly regulates the strength of the intrinsic inward rectification. Furthermore, triple mutant channels retained the extrinsic mechanism of inward rectification at pH 7.4, as can be blocked by spermine, but lost the ability to respond to elevated levels of PIP_2, unlike wild-type channels. Interestingly, whole-cell recordings of wild-type and triple mutant channels imply that the mechanism of intrinsic inward rectification is an important contributor to the overall rectification of Kir4.1/Kir5.1 channels in basal conditions.

2025-02-01·Neurological Sciences

Expanding the genotypic and phenotypic spectrum of EAST/SeSAME syndrome: identification of a novel homozygous mutation (c.194 G > A) in KCNJ10 gene

Article

作者: Esmaeili, Fatemeh ; Dalvand, Leyla ; Khoshnazar, Shivasadat ; Vafaeie, Farzane ; Khorasani, Nima Norouzi ; Moghaddam, Bahareh Esmaeili ; Attari, Rezvan ; Saeidi, Kolsoum ; Jafarinejad-Farsangi, Saeideh ; Yari, Abolfazl ; Gohari, Atieh Karimi

INTRODUCTIONEAST/SeSAME syndrome is an ultra-rare disease characterized by seizures, epilepsy, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance and arises due to deleterious variants disrupting the function of the KCNJ10 gene. In this study, we investigated the clinical symptoms and genetic cause of the disease in a 10-year-old Iranian girl who presented with neurological, hearing, and renal problems.METHODSMagnetic resonance imaging (MRI), electroencephalography (EEG), and laboratory tests were performed to evaluate the clinical characteristics of the proband. Distinctively, disease-causing variants were identified using whole-exome sequencing (WES). Subsequently, in-silico analysis was conducted to forecast the pathogenic potential of the identified variant. ClusPro 2.0 and GROMACS software were used for computational docking and molecular dynamic simulation (MDS), respectively. EEG findings revealed epileptic signs.RESULTSBrain MRI scan revealed no abnormalities. Through the application of WES, we detected a homozygous missense variant (NM_002241.5, c.194G > A, p.R65H) in the KCNJ10 gene. Direct sequencing detected this variant in a heterozygous state in the proband's parents. Additionally, this variant was detected in the aborted fetus of the family in a homozygous state. Computational analysis predicted that this variant would cause disease. Protein-protein docking analysis revealed that the p.R65H mutation significantly affects the binding pattern between KCNJ10 and KCNJ16 proteins. MDS demonstrated that the p.R65H variant notably altered the KCNJ10 protein structure, flexibility, stability, and degree of compaction.CONCLUSIONThe detection of this variant broadens the range of KCNJ10 gene mutations linked to EAST/SeSAME syndrome, emphasizing the critical role of genetic testing in diagnosing this condition.

2025-02-01·American Journal of Physiology-Renal Physiology

Kir5.1 regulates Kir4.2 expression and is a key component of the 50-pS inwardly rectifying potassium channel in basolateral membrane of mouse proximal tubules

Article

作者: Duan, Xin-Peng ; Ding, Zheng ; Chowdhury, Tanzina ; Lin, Dao-Hong ; Zhang, Cheng-Biao ; Wang, Wen-Hui

Our study provides direct evidence for the notion that Kir5.1 is a key component of a 50–60 pS inwardly-rectifying-K+ channel, a main type K+ channel in the basolateral-membrane of PT. Also, we demonstrate that deletion of Kir5.1 decreased Kir4.2 protein expression including the basolateral-membrane in PT. Finally, depolarization of PT-membrane- potential in Kir5.1-knockout mice suggests that Kir4.2 alone is not able to sustain basolateral K+ conductance of the PT in the absence of Kir5.1.

项与 Kir5.1 x 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/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