KCa2.3

更新于：2025-05-07

基本信息

别名

hSK3、K3、KCa2.3

+ [9]

简介

Small conductance calcium-activated potassium channel that mediates the voltage-independent transmembrane transfer of potassium across the cell membrane through a constitutive interaction with calmodulin which binds the intracellular calcium allowing its opening (PubMed:12808432, PubMed:20562108, PubMed:31155282, PubMed:36502918). The current is characterized by a voltage-independent activation, an intracellular calcium concentration increase-dependent activation and a single-channel conductance of 10 picosiemens (PubMed:12808432, PubMed:20562108, PubMed:31155282, PubMed:36502918). Also presents an inwardly rectifying current, thus reducing its already small outward conductance of potassium ions, which is particularly the case when the membrane potential displays positive values, above + 20 mV (PubMed:12808432). Activation is followed by membrane hyperpolarization. Thought to regulate neuronal excitability by contributing to the slow component of synaptic afterhyperpolarization (By similarity). Does not function as a small conductance calcium-activated potassium channel (Probable). Selectively suppresses endogenous KCNN3 currents, in a dominant-negative fashion by decreasing the abundance of functional channels in the plasma membrane, possibly by selectively coassembling with and sequestering native KCNN3 protein in intracellular compartments (PubMed:12808432). This dominant inhibitory effect extends to other members of the SK subfamily (PubMed:12808432).

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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551

项与 KCa2.3 相关的文献（医药）

2025-07-01·Brain Research

Plasma and urinary metabolomic signatures differentiate genetic and idiopathic Parkinson’s disease

Article

作者: Valente, Ana Paula ; Cotrin, Juliana Cordovil ; Spitz, Mariana ; Santos-Rebouças, Cíntia Barros ; de Rosso, Ana Lúcia Zuma ; Cadaxo, André Simões ; Pimentel, Márcia Mattos Gonçalves ; Veras, Renato Peixoto ; Pereira, Joao Santos ; Dos Santos Junior, Gilson Costa

Parkinson's disease (PD) is marked by alpha-synuclein accumulation and progressive dopaminergic neuron loss. Using Nuclear Magnetic Resonance (NMR)-based metabolomics, we uncovered metabolic disturbances in idiopathic PD (iPD) and PD linked to LRRK2, GBA1, and PRKN variants in a Brazilian ethnically diverse cohort, free of comorbidities, in comparison to healthy, age-matched controls. In plasma, significant PD-associated metabolites included histidine, acetate, acetoacetate, glutamine, glucose, lipids and lipoproteins, N-acetyl-glycoproteins, and sarcosine. Urine samples revealed alterations in creatine, creatinine, L-asparagine, trimethylamine, 3-beta-hydroxybutyrate, isovaleric acid, glutamine, urea, glycine, choline, arginine, and cysteine in association with PD. Notably, creatine, creatinine, acetate, glucose, and histidine showed pathway influences from LRRK2, GBA1, and PRKN variants. Enrichment analyses highlighted disruptions in glyoxylate and dicarboxylate metabolism (plasma) as well as serine, threonine, and glycine metabolism (urine). Additionally, a metabolite-gene-disease interaction network identified 15 genes associated with PD that interact with key metabolites, highlighting MAPT, SNCA, RERE, and KCNN3 as key players in both plasmaandurine. NMR in saliva samples did not show significant differences between PD groups and controls. Our findings underscore PD-associated metabolites, particularly related to arginine metabolism, the urea cycle, glutamate metabolism, glucose metabolism, and gut microbiota. These pathways and gene interactions may serve as potential biomarkers for PD diagnosis and precision medicine strategies.

2025-06-01·Biochemical Pharmacology

AMPK phosphorylation of KCa2.3 alleviates angiotensin II-induced endothelial dysfunction

Article

作者: Deng, Xiu-Ling ; Pang, Zheng-Da ; Zhang, Yi ; Wang, Yan ; She, Gang ; Han, Meng-Zhuan ; Bai, Ru-Yue ; Shyy, John Y-J ; Du, Xiao-Jun ; Lai, Bao-Chang ; Sun, Xia

The endothelial small-conductance calcium-activated potassium channels (K_Ca2.3) are indispensable for endothelium-dependent hyperpolarization (EDH) response, mainly in resistance arteries. We recently demonstrated in diet-induced obese mice that adenosine monophosphate-activated protein kinase (AMPK) upregulates endothelial K_Ca2.3 expression and improves endothelial function. However, the molecular mechanism of regulation of K_Ca2.3 by AMPK remains less explored. Using techniques of bioinformatics, molecular biology and wire myograph system, we examined K_Ca2.3 phosphorylation by AMPK in human umbilical vein endothelial cells (HUVECs), human embryonic kidney 293 (HEK-293T) cells and second-order mesenteric resistance arteries from angiotensin II-induced hypertensive mice. In HUVECs, treatment with activators of AMPK (AICAR, metformin, and MK-8722) significantly increased phosphorylation of K_Ca2.3 Thr106 (human), which was antagonized by AMPK inhibitor compound C. In HEK-293T cells, K_Ca2.3 current was enhanced by AMPK activation or phosphomimetic mutant K_Ca2.3 (T106D), which was abolished after de-phosphomimetic mutant (T106A) or deletion of K_Ca2.3 of Thr106 site (T106Del). In mice with angiotensin II infusion, 2-week treatment with AICAR or overexpressing phosphomimetic mutant K_Ca2.3 Thr107D (mouse) restored K_Ca2.3-mediated EDH-dependent relaxation in mesenteric resistance arteries together with reversal of early phase hypertension. Our study demonstrates for the first time that AMPK activation mediates K_Ca2.3 phosphorylation in endothelial cells with enhanced channel activity. This effect ameliorates endothelial dysfunction of mesenteric resistance arteries and alleviates angiotensin II-induced early phase hypertension in mice.

2025-04-01·Scandinavian Journal of Immunology

Autoantibodies as Potential Liquid Biopsy Biomarker in Detection of Pancreatic Cancer: A Diagnostic Test Accuracy Review and Meta‐Analysis

Review

作者: Yu, Jinyao ; Ma, Siyao ; Gao, Yuyi ; Ye, Hua ; Wu, Yangxue ; Wang, Keyan ; Liu, Yuqi ; Wu, Wanyang ; Shi, Jianxiang

ABSTRACTAutoantibodies against tumour‐associated antigens (TAA) are promising biomarkers for cancer diagnosis. This systematic review aims to evaluate the diagnostic values of tumour‐associated autoantibodies (TAAbs) in patients with pancreatic cancer. A search was conducted in the PubMed, Web of Science, and Embase databases to collect eligible studies. The primary outcomes included sensitivity, specificity, and accuracy of the test. We used QUADAS‐2 to evaluate the risk of bias in the included studies. Meta‐analysis was performed using MetaDisc 1.4 and STATA 14.0 software to calculate the combined sensitivity and specificity. A total of 49 articles were included in the final analysis that reported over 100 different TAAbs that were studied for the detection of pancreatic cancer. p53, Ezrin, CLDN17, KCNN3, SLAMF7, SLC22A11 and OR51F2 were the most frequently investigated autoantibodies in these studies. Ezrin exhibited better diagnostic performance with the pooled sensitivity, specificity and summary area under the receiver operating characteristic (SROC) curves being 56%, 88% and 0.90, respectively. Moreover, certain autoantibody combinations achieved substantially higher sensitivity at reasonably high levels of specificity. For example, the combination of Ezrin and ENOA1.2 autoantibodies with CA19.9 yielded sensitivity, specificity and area under the SROC curve of 100%, 92% and 0.96, respectively. TAAb is a promising diagnostic biomarker for early detection of PC, especially when combining TAAb with other markers. The promising candidate markers identified in this review deserve further validation in a broad screening population.

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