更新于：2024-11-01

KCa2.3

更新于：2024-11-01

基本信息

别名

hSK3、K3、KCa2.3

+ [9]

简介

Forms a voltage-independent potassium channel activated by intracellular calcium (PubMed:31155282, PubMed:20562108). Activation is followed by membrane hyperpolarization (By similarity). Thought to regulate neuronal excitability by contributing to the slow component of synaptic afterhyperpolarization (By similarity).

关联

项与 KCa2.3 相关的药物

NSD-8011

靶点

KCNN2 x KCa2.3

作用机制

KCNN2 inhibitors [+1]

在研机构

Cadent Therapeutics, Inc.

原研机构

NTG Nordic Transport Group A/S

在研适应症

共济失调

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 KCa2.3 相关的临床结果

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100 项与 KCa2.3 相关的转化医学

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0 项与 KCa2.3 相关的专利（医药）

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571

项与 KCa2.3 相关的文献（医药）

2024-12-01·Reproductive BioMedicine Online

The relationship between Sjögren's syndrome and recurrent pregnancy loss: a bioinformatics analysis

Article

作者: Liu, Cai ; Wang, Fang ; Huo, Huyan ; Zeng, Xianghui ; Mu, Fangxiang

RESEARCH QUESTIONAs Sjögren's syndrome is an autoimmune disease and an essential factor in recurrent pregnancy loss (RPL), are there gene-related relationships between the pathogenesis of Sjögren's syndrome and RPL?DESIGNThe gene datasets for Sjögren's syndrome and RPL were obtained from the Gene Expression Omnibus database, and the co-expression modules and shared differentially expressed genes were identified through weighted gene co-expression network analysis (WGCNA) and limma analysis based on sample size. Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes analyses were applied to reveal the hidden biological pathways. Additionally, shared hub gene identification, gene set enrichment analysis, association of the hub gene with ferroptosis and immunity, drug sensitivity analysis, single-cell RNA sequencing analysis, and construction of the competing endogenous RNA (ceRNA) network were conducted.RESULTSBy intersecting the genes from WGCNA and limma analysis, one shared hub gene (KCNN3) was derived, exhibiting up-regulation in Sjögren's syndrome and RPL. There was a positive relationship between KCNN3 and the immune-related gene TLR2. The ceRNA network revealed that XIST was the most shared long non-coding RNA, which may bind competitively with eight microRNA to regulate the expression of KCNN3. Forty-eight drugs were found to be strongly associated with KCNN3 expression, including estramustine and cyclosporine. Moreover, KCNN3 exhibited high expression in RPL endothelial cells of villous tissue.CONCLUSIONSThis is one of the first studies to reveal that Sjögren's syndrome shares common biological pathways with RPL. KCNN3 was identified as the hub gene associated with Sjögren's syndrome and RPL, and may be a new target for mechanistic studies on Sjögren's syndrome and RPL.

2024-09-01·American Journal of Physiology-Gastrointestinal and Liver Physiology

Modulation of intracellular calcium activity in interstitial cells of Cajal by inhibitory neural pathways within the internal anal sphincter

Article

作者: Ni Bhraonain, Emer P ; Gould, Thomas W. ; Hannigan, Karen I. ; Hannigan, Karen I ; Keef, Kathleen D. ; Gould, Thomas W ; Cobine, Caroline A. ; Keef, Kathleen D ; Ni Bhraonain, Emer P. ; Cobine, Caroline A

Two intramuscular interstitial cells of Cajal (ICC-IM) subtypes exist within the internal anal sphincter (IAS). This study provides the first evidence for direct coupling between nitrergic motor neurons and both ICC-IM subtypes as well as indirect coupling between purinergic inputs and Type II ICC-IM. The spatiotemporal properties of whole cell Ca2+ transients in Type II ICC-IM mimic those of smooth muscle cells (SMCs), suggesting that ICC-IM modulate the activity of SMCs via their joint participation in a SIP syncytium (SMCs, ICC, and PDGFRα+ cells).

2024-09-01·JAMA Psychiatry

Key Roles of CACNA1C/Cav1.2 and CALB1/Calbindin in Prefrontal Neurons Altered in Cognitive Disorders

Article

作者: Krienen, Fenna M ; Datta, Dibyadeep ; Rakic, Pasko ; Lewis, David A ; Arnsten, Amy F T ; Uchendu, Stacy ; Wang, Min ; Berretta, Sabina ; Perone, Isabella ; Woo, Elizabeth ; Goldman, Melissa ; Arellano, Jon ; Morozov, Yury ; McCarroll, Steven A ; Duque, Alvaro ; Yang, Shengtao ; Gonzalez-Burgos, Guillermo ; Ling, Emi ; van Dyck, Christopher H ; O'Dell, Ryan ; Joyce, Mary Kate P ; Murray, John

ImportanceThe risk of mental disorders is consistently associated with variants in CACNA1C (L-type calcium channel Cav1.2) but it is not known why these channels are critical to cognition, and whether they affect the layer III pyramidal cells in the dorsolateral prefrontal cortex that are especially vulnerable in cognitive disorders.ObjectiveTo examine the molecular mechanisms expressed in layer III pyramidal cells in primate dorsolateral prefrontal cortices.Design, Setting, and ParticipantsThe design included transcriptomic analyses from human and macaque dorsolateral prefrontal cortex, and connectivity, protein expression, physiology, and cognitive behavior in macaques. The research was performed in academic laboratories at Yale, Harvard, Princeton, and the University of Pittsburgh. As dorsolateral prefrontal cortex only exists in primates, the work evaluated humans and macaques.Main Outcomes and MeasuresOutcome measures included transcriptomic signatures of human and macaque pyramidal cells, protein expression and interactions in layer III macaque pyramidal cells using light and electron microscopy, changes in neuronal firing during spatial working memory, and working memory performance following pharmacological treatments.ResultsLayer III pyramidal cells in dorsolateral prefrontal cortex coexpress a constellation of calcium-related proteins, delineated by CALB1 (calbindin), and high levels of CACNA1C (Cav1.2), GRIN2B (NMDA receptor GluN2B), and KCNN3 (SK3 potassium channel), concentrated in dendritic spines near the calcium-storing smooth endoplasmic reticulum. L-type calcium channels influenced neuronal firing needed for working memory, where either blockade or increased drive by β1-adrenoceptors, reduced neuronal firing by a mean (SD) 37.3% (5.5%) or 40% (6.3%), respectively, the latter via SK potassium channel opening. An L-type calcium channel blocker or β1-adrenoceptor antagonist protected working memory from stress.Conclusions and RelevanceThe layer III pyramidal cells in the dorsolateral prefrontal cortex especially vulnerable in cognitive disorders differentially express calbindin and a constellation of calcium-related proteins including L-type calcium channels Cav1.2 (CACNA1C), GluN2B-NMDA receptors (GRIN2B), and SK3 potassium channels (KCNN3), which influence memory-related neuronal firing. The finding that either inadequate or excessive L-type calcium channel activation reduced neuronal firing explains why either loss- or gain-of-function variants in CACNA1C were associated with increased risk of cognitive disorders. The selective expression of calbindin in these pyramidal cells highlights the importance of regulatory mechanisms in neurons with high calcium signaling, consistent with Alzheimer tau pathology emerging when calbindin is lost with age and/or inflammation.

项与 KCa2.3 相关的新闻（医药）

2024-07-17

·生物探索

Sci Adv丨徐平稳/何彦林/王春梅/叶慧合作发现27-羟基胆固醇通过作用于POMC神经元表达的雌激素受体α调控摄食行为

引言 1978年Andrew Kandutsch及其同事在“胆固醇稳态的氧固醇假说”中首次提出氧固醇 (Oxysterol) 是胆固醇生物合成反馈调节的主要介质【1】。氧固醇是胆固醇的代谢产物，在外周组织中产生，能够反馈调节胆固醇的合成和吸收【2-3】。27-羟基胆固醇 (27HC) 是人体循环中最丰富的氧固醇之一。有趣的是，研究表明，27HC是体内合成的内源选择性雌激素受体调节剂 (selective estrogen receptor modulators，SERM)【4】，能够作用于雌激素受体α和β (estrogen receptorα/β, ERα/β)。而且，相对于胆固醇来说，27HC特殊的化学结构使其能够更好地通过磷脂膜扩散，从而穿过血脑屏障 (blood-brain barrier，BBB)【5】。值得关注的是，在大脑中表达的雌激素受体在能量和脂质稳态调节中起到致关重要的作用【6-7】。目前，已有相关文献提出，27HC可以作为信号载体将血液中胆固醇水平反馈到中枢神经，以调节各种代谢功能，包括胆固醇代谢【8】、神经衰老【9】、神经退化【10】、炎症反应【11】和神经元葡萄糖摄取【12】。然而，27HC是否是通过雌激素受体对大脑神经元活性产生影响从而调节全身能量稳态，目前尚不可知。 7月12日，来自伊利诺伊大学芝加哥分校 (University of Illinois Chicago，UIC) 的徐平稳博士，路易斯安那州立大学潘宁顿生物医学研究中心（Pennington Biomedical Research Center ，PBRC）的何彦林博士，美国贝勒医学院（Baylor College of Medicine，BCM）的王春梅博士，以及新加坡南洋理工大学（Nanyang Technological University，NTU）的叶慧博士研究团队，合作在Science Advances杂志上发表了研究成果：27-Hydroxycholesterol acts on estrogen receptor αexpressed by POMC neurons in the arcuate nucleus to modulate feeding behavior。该研究发现，27HC通过作用于下丘脑弓状核（The arcuate nucleus， ARH）阿黑皮素原（proopiomelanocortin ，POMCARH）神经元中表达的ERα抑制小电导钙离子激活钾通道（the small conductance of the calcium-activated potassium，SK）来激活该神经元，从而迅速地抑制食物摄入。这一27HC/ERα/SK/POMC信号通路可能是一种关键的负反馈机制。在高胆固醇食物摄入导致血液中胆固醇迅速上升的情况下，它能够通过减少食物摄入来有效降低血液中的胆固醇含量。这一成果揭示了当人们摄入高脂/油腻食物后，感到食欲降低的潜在原因之一。为了研究27HC是否能够通过中枢神经调节能量代谢，该合作团队首先比较了单次腹腔 (IP) 以及脑室（ICV）注射27HC照成的小鼠的摄食行为以及相关代谢参数的变化。他们通过记录并分析食物摄入量，摄入间隔时长，累积食物消耗量，呼吸商，氧气消耗量，二氧化碳产生量以及脂肪利用率等指标，发现27HC的外周和中枢给药均可引起小鼠的食欲减退，并且脑室注射导致的厌食作用还会引起小鼠全身底物利用方式从碳水化合物到脂肪的急剧转变。为了进一步研究27HC的中枢作用机理，研究人员首先利用转基因小鼠模型（ERα-ZsGreen）荧光标记ERα表达的神经元，并通过小鼠脑切片以及免疫组织化学染色发现27HC能够激活在下丘脑弓状核（ARH）中表达的ERα神经元。有趣的是，在这一区域，大部分的ERα表达在抑制采食的POMC神经元而非促进采食的刺鼠相关肽AGRP神经元。随后，研究人员利用POMCtdTOMATO小鼠模型结合电生理技术验证了27HC能够通过结合ERα的方式激活下丘脑弓状核中分布的POMC神经元（POMCARH）。这一实验结果表明POMC神经元以及ERα可能是27HC中枢调控食欲的两个重要介质。为了验证这一设想，研究人员脑室注射了27HC + BHPI (ERα拮抗剂) 或27HC + SHU9119 (POMC下游信号MC3/4-R的拮抗剂)，结果标明，BHPI和SHU9119均有效阻断了27HC 对小鼠采食行为的抑制作用。该药理学阻断实验进一步证明了POMC神经元以及ERα的关键作用。随后，研究人员为了更具体地检验POMC神经元中表达的ERα（ERαPOMC）在27HC采食调控中的作用，他们利用了Cre-LoxP重组技术，特异性地从POMC神经元中敲除ERα基因。实验结果表明，在ERαPOMC被敲除的情况下，由27HC引发的厌食效应显著降低。这一结果证实了ERαPOMC在27HC采食调节中起到不可或缺的作用。同时，研究人员利用化学遗传学技术（Designer Receptors Exclusively Activated by Designer Drugs，DREADD）特异性地抑制POMCARH神经元活性，随后对小鼠的采食行为进行监测。结果表明，POMCARH 静默能显著降低27HC的厌食作用。因此，研究人员得出结论，POMCARH神经元激活是27HC降低采食的关键一环。值得注意的是，SK3（一种 SK 离子通道的亚型）在POMCARH神经元中大量表达，是其细胞内信号传导的关键组成部分[13]。并且有报道指出，SK3离子通道能够参与整合神经元介导的食物摄入和外周代谢信号 (包括白脂素和雌激素) 的调节【14】。为进一步揭示27HC激活POMCARH神经元并调控食欲的神经元内分子作用机制。研究人员同样利用Cre-LoxP技术，特异性地敲除了SK3基因在POMCARH神经元中的表达。随后的电生理记录以及小鼠采食行为的监测实验均证实了SK3离子通路在27HC激活POMCARH神经元并抑制食欲中的关键角色。模式图 (Credit: Science Advances) 综上所述，本研究通过电生理学，化学遗传学，基因敲除等多种技术，揭示了27HC通过作用于ERα，抑制SK3离子通道，激活POMCARH神经元并且抑制食欲，从而维持体内胆固醇动态平衡的效果。参考文献 A. A. Kandutsch, H. W. Chen, H. J. Heiniger, Biological activity of some oxygenated sterols. Science 201, 498-501 (1978) S. Gill, R. Chow, A. J. Brown, Sterol regulators of cholesterol homeostasis and beyond: the oxysterol hypothesis revisited and revised. Prog Lipid Res 47, 391-404 (2008). N. B. Javitt, 25R,26-Hydroxycholesterol revisited: synthesis, metabolism, and biologic roles. J Lipid Res 43, 665-670 (2002) M. Umetani, P. W. Shaul, 27-Hydroxycholesterol: the first identified endogenous SERM. Trends in Endocrinology & Metabolism 22, 130-135 (2011). M. Hilsch, I. Haralampiev, P. Muller, D. Huster, H. A. Scheidt, Membrane properties of hydroxycholesterols related to the brain cholesterol metabolism. Beilstein J Org Chem 13, 720-727 (2017). P. Xu, X. Cao, Y. Xu, Targeting brain estrogen receptor for binge eating. Oncotarget 6, 23044-23045 (2015). 32. Y. Xu, M. Lopez, Central regulation of energy metabolism by estrogens. Mol Metab 15, 104-115 (2018) D. D. Zhang et al., 27-Hydroxycholesterol contributes to disruptive effects on learning and memory by modulating cholesterol metabolism in the rat brain. Neuroscience 300, 163-173 (2015). J. Liu et al., Resveratrol Alleviates 27-Hydroxycholesterol-Induced Senescence in Nerve Cells and Affects Zebrafish Locomotor Behavior via Activation of SIRT1-Mediated STAT3 Signaling. Oxid Med Cell Longev 2021, 6673343 (2021). M. A. Ismail et al., 27-Hydroxycholesterol impairs neuronal glucose uptake through an IRAP/GLUT4 system dysregulation. J Exp Med 214, 699-717 (2017). W. W. Ma, C. Q. Li, L. Zhao, Y. S. Wang, R. Xiao, NF-kappaB-mediated inflammatory damage is differentially affected in SH-SY5Y and C6 cells treated with 27-hydroxycholesterol. Food Sci Nutr 7, 1685-1694 (2019). R. Loera-Valencia et al., Hypercholesterolemia and 27-Hydroxycholesterol Increase S100A8 and RAGE Expression in the Brain: a Link Between Cholesterol, Alarmins, and Neurodegeneration. Mol Neurobiol 58, 6063-6076 (2021). M. Yu et al., SK3 in POMC neurons plays a sexually dimorphic role in energy and glucose homeostasis. Cell Biosci 12, 170 (2022). Feng B, Liu H, Mishra I, et al. Asprosin promotes feeding through SK channel–dependent activation of AgRP neurons[J]. Science Advances, 2023, 9(8): eabq6718. http://doi.org/10.1126/sciadv.adi4746 责编|探索君排版|探索君文章来源|“BioArt” 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 Cell | 是什么决定了细胞的大小？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 CRISPR技术进化史 | 24年Cell综述

临床研究