更新于：2024-11-01

Kir3.2

更新于：2024-11-01

基本信息

别名

BIR1、G protein-activated inward rectifier potassium channel 2、GIRK-2

+ [11]

简介

This potassium channel may be involved in the regulation of insulin secretion by glucose and/or neurotransmitters acting through G-protein-coupled receptors. 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.

关联

项与 Kir3.2 相关的药物

GAT1508

靶点

Kir3.1 x Kir3.2

作用机制

Kir3.1 激活剂 [+1]

在研机构

Northeastern University

原研机构

Northeastern University

在研适应症

创伤后应激障碍

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 Kir3.2 相关的临床结果

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100 项与 Kir3.2 相关的转化医学

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0 项与 Kir3.2 相关的专利（医药）

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602

项与 Kir3.2 相关的文献（医药）

2024-11-01·MicroRNA

Glioblastoma Multiforme miRNA based Comprehensive Study to Validate Phytochemicals for Effective Treatment against Deadly Tumour through In Silico Evaluation

Article

作者: Tiwari, Archana ; Khan, Roji Begam ; Tiwari, Shikha ; Shrivastava, Adesh ; Jarkharya, Aryan ; Chowdhary, Rashmi

Background:Glioblastoma Multiforme (GBM) is a prevalent and deadly type of pri-mary astrocytoma, constituting over 60% of adult brain tumors, and has a poor prognosis, with a high relapse rate within 7 months of diagnosis. Despite surgical, radiotherapy, and chemotherapy treatments, GBM remains challenging due to resistance. MicroRNA (miRNAs) control gene ex-pression at transcriptional and post-transcriptional levels by targeting their messenger RNA (mRNA), and also contribute to the development of various neoplasms, including GBM.Methods:The present study focuses on exploring the miRNAs-based pathogenesis of GBM and evaluating most potential plant-based therapeutic agents with in silico analysis. Gene chips were retrieved from the Gene Expression Omnibus (GEO) database, followed by the Robust- Rank-Aggereg algorithm to determine the Differentially Expressed miRNAs (DEMs). The predicted targets were intersected with the GBM-associated genes, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the overlapping genes was performed. At the same time, five phytochemicals were selected for the Connectivity map (CMap), and the most efficient ones were those that had undergone molecular docking analysis to obtain the potential therapeutic agents.Results:The hsa-miR-10b, hsa-miR-21, and hsa-miR-15b were obtained, and eight genes were found to be associated with glioma pathways; VSIG4, PROCR, PLAT, and ITGB2 were upregulated while, CAMK2B, PDE1A, GABRA1, and KCNJ6 were downregulated. The drugs Resveratrol and Quercetin were identified as the most prominent drugs.Conclusion:These miRNAs-based drugs can be used as a curative agent for the treatment of GBM. However, in vivo, experimental data, and clinical trials are necessary to provide an alter-native to conventional GBM cancer chemotherapy.

2024-10-01·Molecules and Cells

Cellular and metabolic function of GIRK1 potassium channels expressed by arcuate POMC and NPY/AgRP neurons

Article

作者: Sohn, Jong-Woo ; Choi, Yeeun ; Yoo, Eun-Seon ; Oh, Youjin

It is well known that the G protein-gated inwardly rectifying K⁺ (GIRK) channels are critical to maintain excitability of central neurons. GIRK channels consist of 4 subunits and GIRK1/GIRK2 heterotetramers are considered to be the neuronal prototype. We previously reported the metabolic significance of GIRK2 subunits expressed by the neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons of the arcuate nucleus of the hypothalamus (ARH). However, the role of GIRK1 subunits expressed by the neurons of ARH remains to be determined. In this study, we delineated the contribution of GIRK1 channel subunits to the excitability of the pro-opiomelanocortin (POMC) and NPY/AgRP neurons of the ARH. We further assessed the metabolic function of GIRK1 subunits expressed by these neurons. Our results provide insight how GIRK channels regulate arcuate POMC and NPY/AgRP neurons and shape metabolic phenotypes.

2024-09-02·Plant Physiology

RING/U-box E3 protein BIR1 interacts with and ubiquitinates barley growth repressor BROAD LEAF1

Article

作者: McKim, Sarah ; Lenhard, Michael ; Hoffie, Iris ; Hensel, Götz ; Prag, Gali ; Kumlehn, Jochen ; Soltani, Ouad ; Kappel, Christian ; Jöst, Moritz

AbstractEstablishment of final leaf size in plants relies on the precise regulation of 2 interconnected processes, cell division and cell expansion. The barley (Hordeum vulgare) protein BROAD LEAF1 (BLF1) limits cell proliferation and leaf growth in the width direction. However, how the levels of this potent repressor of leaf growth are controlled remains unclear. Here, we used a yeast 2-hybrid screen to identify the BLF1-INTERACTING RING/U-BOX 1 (BIR1) E3 ubiquitin ligase that interacts with BLF1 and confirmed the interaction of the 2 proteins in planta. Inhibiting the proteasome caused overaccumulation of a BLF1-eGFP fusion protein when co-expressed with BIR1, and an in vivo ubiquitination assay in bacteria confirmed that BIR1 can mediate ubiquitination of BLF1 protein. Consistent with regulation of endogenous BLF1 in barley by proteasomal degradation, inhibition of the proteasome in BLF1-vYFP–expressing barley plants caused an accumulation of the BLF1 protein. The BIR1 protein co-localized with BLF1 in nuclei and appeared to reduce BLF1 protein levels. Analysis of bir1-1 knockout mutants suggested the involvement of BIR1 in leaf growth control, although mainly on leaf length. Together, our results suggest that proteasomal degradation, in part mediated by BIR1, helps fine-tune BLF1 protein levels in barley.

项与 Kir3.2 相关的新闻（医药）

2022-08-25

·生物谷

《细胞》子刊：APOE4让小胶质细胞变得“油腻”，神经元活动被抑制！

这个发现未来或许还能帮助研究人员构建模拟AD后期的研究模型。我们都知道，与晚发的非家族性阿尔茨海默病（AD）关联最强的遗传因素就是APOE4[1,2]，有大约14%的人携带这一遗传变异，而从另一个角度来看，在整个AD患者群体中，约50%都是APOE4携带者，就是如此重要的一个遗传变异，但我们对它如何影响AD的发生发展仍然还不清楚[3]。来自美国麻省理工学院的蔡立慧教授的团队一直致力于研究APOE4对大脑中各种类型细胞影响。 2018年时，他们发现，APOE4会导致神经元产生大量β淀粉样多肽42，导致神经元过度活跃，除此之外，小胶质细胞和星形胶质细胞也会受到影响，导致胆固醇积累和炎症，无法清除沉积的β淀粉样蛋白[4]。2021年，他们将研究结果继续推进，证明了APOE4会使星形胶质细胞的脂质代谢能力严重受损[5]。时间来到2022年，这一次，轮到了小胶质细胞。蔡教授的团队发现，APOE4也破坏了小胶质细胞的脂质代谢能力，这导致脂质分子，尤其是胆固醇的积累，它们会与神经元细胞膜中特定类型的钾离子通道结合，从而抑制神经元放电，神经元兴奋性下降，这是会在AD后期出现的一种现象。另外，脂质的积累还会导致炎症，神经炎症也是已知的促进AD进展的因素之一。这个发现未来或许还能帮助研究人员构建模拟AD后期的研究模型。研究结果发表在了《细胞·干细胞》杂志上[6]。研究依托于研究团队此前利用诱导性多能干细胞（iPSCs）的CRISPR-Cas9基因组编辑，可以衍生出除了APOE等位基因不同，其他基因相同的等基因细胞系，包括神经元、星形胶质细胞和小胶质细胞[4]。大脑中的小胶质细胞高表达嘌呤能受体P2RY12，嘌呤能信号是小胶质细胞趋化、吞噬和产生促炎因子的重要调节信号，P2RY12能够感知细胞外的能量分子（ADP和ATP）。很多可溶性神经元因子也参与小胶质细胞对神经元活动的监测，例如CX3CL1-CX3CR1信号轴。另外，小胶质细胞还表达大量神经递质受体，介导神经元-小胶质细胞通讯。研究团队用iPSCs衍生出的小胶质细胞样细胞（iMGLs）也同样表达这些重要受体，与小胶质细胞高度一致。 iMGLs表达典型的小胶质细胞受体为了确定APOE4对神经元-小胶质细胞通讯功能的影响，研究人员同时构建了APOE3和APOE4 iMGLs，APOE3与APOE4仅差一个氨基酸，但它对AD的影响就是中性的了。通过使用不同类型的选择性抑制剂进行重复实验，研究人员发现，嘌呤能信号在APOE4 iMGLs中受损，由于嘌呤能受体P2RY12的减少与小胶质细胞激活状态有关，研究人员推断，APOE4 iMGLs的监测状态发生了改变，削弱了对神经元活动的监测。转录谱分析进一步坐实了他们的推断。APOE4 iMGLs转录反应更强，在HIF-1和JAK-STAT信号，以及细胞因子-细胞因子受体相互作用方面显著富集，提示其具有强烈的促炎反应。细胞内钙离子信号通路的诱导减少，钙瞬态下降。P2RY12表达水平显著降低，而与小胶质细胞“高度警觉”状态有关的P2RY6则没有显著增加。此外，还有很多稳态基因表达也显著减少，包括CX3CR1和CSF1R。这些结果提供了分子层面的佐证，接下来，把目光挪到细胞层面。我们知道，促炎刺激可以诱导小胶质细胞的代谢转换，从氧化磷酸化（OXPHOS）转换为糖酵解[7]，研究人员也确实发现，APOE4 iMGLs中葡萄糖转运蛋白GLUT3的水平有微小但显著的增加，另外，刚刚提到过的显著富集的HIF-1信号也正好是糖酵解的主要转录调控因子[8]。能量消耗和脂肪酸氧化损伤与活化小胶质细胞内脂质积累有关，在氧化磷酸化相关基因表达减少的同时，研究人员确实也观察到了APOE4 iMGLs中脂质分解代谢过程相关的差异表达基因和膜脂肪酸转运蛋白CD36减少。氧化磷酸化相关基因表达有显著的下降对脂滴进行染色后发现，APOE4 iMGLs中脂滴含量显著增加，G蛋白激活下游钙信号通路可以通过激活蛋白激酶A和C（PKA和PKC）促进脂质分解，与这一重要机制相一致的，研究人员观察到APOE4 iMGLs中编码PKA和PKC催化和调控结构域的基因表达减少。 APOE作为大脑中的主要胆固醇转运蛋白，介导神经元和胶质细胞之间的胆固醇及其他脂质的传递。APOE4 iMGLs培养物上清液中富含APOE和胆固醇，之前的研究认为，胆固醇的增加与APOE4胶质细胞的脂质转运减少有关[9]，但研究人员推断，细胞外的脂质积累也可能是相对更严重的脂质细胞内流缺陷的“产物”。为了验证这个推断，他们将APOE3和APOE4 iMGLs同时和人血浆中分离出的低密度脂蛋白胆固醇（LDL）共培养，与APOE3相比，APOE4 iMGLs对LDL的细胞摄取大大减少。与APOE3相比，APOE4 iMGLs的脂质摄取大大减少对于神经元来说，外源性胆固醇的加入使得静息膜电位发生了超极化，电流-电压曲线也发生了变化，内向整流钾离子（Kir）电流增强，而Kir电流的增强正是静息膜电位超极化的原因，并且会降低神经元兴奋性。在Kir通道中，由KCNJ9基因编码的Kir3.3通道（GIRK3）大量表达，和其他Kir通道一样可以调节神经元兴奋性，发挥功能时降低神经元活性，丧失功能时则增加神经元活性，而且GIRK通道刚好是脂质门控通道，在神经元中，胆固醇会增强它的活性，从而降低神经元兴奋性。GIRK通道位于神经元细胞膜上富含胆固醇的微结构域，也就是脂筏，而在APOE4 iMGLs中，脂筏增加。研究人员查阅了已经公开发表的AD患者的snRNA测序数据[10]，发现与没有AD的对照组相比，AD患者的兴奋性神经元中GIRK2和GIRK3的水平显著增加。也就是说，APOE4使得小胶质细胞的脂质代谢能力受损，这导致了脂质分子“流落在外”，积累的脂质分子使得神经元细胞膜中的Kir电流增强，使得静息膜电位超极化，降低了神经元兴奋性。研究人员尝试使用能够抑制脂滴形成的三氮菌素C处理了APOE4小胶质细胞，成功减少了脂质积累，神经元活动得以恢复正常。不过三氮菌素C具有细胞毒性，不适合真的用于治疗AD，但这个研究为我们指明了一个新的方向，即恢复脂质稳态，以对抗APOE4对神经胶质细胞和神经元的影响。研究的第一作者Matheus B. Victor博士表示，恢复大脑中不同类型细胞的脂质稳态至关重要，但这不是一件容易的事，此前他们发现胆碱可能有这种潜力，未来，还需要进行更多的探索。参考文献： [1] Liu C C, Kanekiyo T, Xu H, et al. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy[J]. Nature Reviews Neurology, 2013, 9(2): 106-118. [2] Yamazaki Y, Zhao N, Caulfield T R, et al. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies[J]. Nature Reviews Neurology, 2019, 15(9): 501-518. [3] https://news.mit.edu/2022/microglia-apoe4-alzheimers-0804 [4] Lin Y T, Seo J, Gao F, et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types[J]. Neuron, 2018, 98(6): 1141-1154. e7. [5] Sienski G, Narayan P, Bonner J M, et al. APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia[J]. Science translational medicine, 2021, 13(583): eaaz4564. [6] Victor M B, Leary N, Luna X, et al. Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity[J]. Cell Stem Cell, 2022, 29(8): 1197-1212. e8. [7] Lauro C, Limatola C. Metabolic reprograming of microglia in the regulation of the innate inflammatory response[J]. Frontiers in Immunology, 2020, 11: 493. [8] Cheng S C, Quintin J, Cramer R A, et al. mTOR-and HIF-1α–mediated aerobic glycolysis as metabolic basis for trained immunity[J]. Science, 2014, 345(6204): 1250684. [9] Liang S A, Qian L, Pipalia N H, et al. Cholesterol and matrisome pathways dysregulated in human APOE ε4 glia[J]. Preprint at bioRxiv, 2019. [10] Mathys H, Davila-Velderrain J, Peng Z, et al. Single-cell transcriptomic analysis of Alzheimer’s disease[J]. Nature, 2019, 570(7761): 332-337.