ion channels

离子通道
  • 文章类型: Journal Article
    机械敏感性离子通道瞬时受体电位香草素4(TRPV4)和PIEZO1转导软骨细胞中机械信号的生理和超生理幅度,分别。TRPV4激活促进软骨形成,而PIEZO1通过超生理变形激活导致细胞死亡。这些通道的激活离散地驱动基因表达变化以改变细胞行为的机制仍有待确定。迄今为止,没有研究对比这些通道激活的转录组反应,也没有任何已发表的数据试图将这些转录组与细胞功能的改变联系起来.这项研究使用RNA测序来全面研究与TRPV4或PIEZO1激活相关的转录组,揭示TRPV4和PIEZO驱动不同的转录组,并且还表现出独特的共同调节的基因簇。值得注意的是,通过超生理变形激活PIEZO1可诱导与白细胞介素(IL)-1反应性转录组重叠的短暂炎症谱,并包含与软骨降解和骨关节炎进展相关的基因.然而,TRPV4和PIEZO1也显示出引起合成代谢作用。PIEZO1表达在无负载条件下促进了软骨形成前转录组,每天用PIEZO1激动剂Yoda1治疗可在体外显着增加硫酸化糖胺聚糖沉积。这些发现强调了软骨细胞中TRPV4和PIEZO1激活的广泛“机械组”的存在,提示PIEZO1在软骨细胞的生理和病理反应中的复杂作用。PIEZO1和TRPV4(不同于IL-1诱导的炎症)特有或共有的转录组特征的鉴定可以为将来针对这些通道的治疗设计提供指导,用于骨关节炎的管理和治疗。
    The mechanosensitive ion channels Transient Receptor Potential Vanilloid 4 (TRPV4) and PIEZO1 transduce physiologic and supraphysiologic magnitudes of mechanical signals in the chondrocyte, respectively. TRPV4 activation promotes chondrogenesis, while PIEZO1 activation by supraphysiologic deformations drives cell death. The mechanisms by which activation of these channels discretely drives changes in gene expression to alter cell behavior remain to be determined. To date, no studies have contrasted the transcriptomic response to activation of these channels nor has any published data attempted to correlate these transcriptomes to alterations in cellular function. This study used RNA sequencing to comprehensively investigate the transcriptomes associated with activation of TRPV4 or PIEZO1, revealing that TRPV4 and PIEZO drive distinct transcriptomes and also exhibit unique co-regulated clusters of genes. Notably, activation of PIEZO1 through supraphysiologic deformation induced a transient inflammatory profile that overlapped with the interleukin (IL)-1-responsive transcriptome and contained genes associated with cartilage degradation and osteoarthritis progression. However, both TRPV4 and PIEZO1 were also shown to elicit anabolic effects. PIEZO1 expression promoted a pro-chondrogenic transcriptome under unloaded conditions, and daily treatment with PIEZO1 agonist Yoda1 significantly increased sulfated glycosaminoglycan deposition in vitro. These findings emphasize the presence of a broad \"mechanome\" with distinct effects of TRPV4 and PIEZO1 activation in chondrocytes, suggesting complex roles for PIEZO1 in both the physiologic and pathologic responses of chondrocytes. The identification of transcriptomic profiles unique to or shared by PIEZO1 and TRPV4 (distinct from IL-1-induced inflammation) could inform future therapeutic designs targeting these channels for the management and treatment of osteoarthritis.
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  • 文章类型: Editorial
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  • 文章类型: Journal Article
    细胞微环境的微观几何形状深刻影响细胞行为,然而,它与普遍表达的机械敏感性离子通道PIEZO1之间的联系仍不清楚。在这里,我们描述了一种荧光微量移液管抽吸测定法,可以实时同时显示细胞内钙动力学和细胞骨架结构,在不同的微量移液管几何形状。通过将弹性壳有限元分析与荧光寿命成像显微镜相结合,并采用PIEZO1特异性转基因红细胞和HEK细胞系,我们证明了抽吸的微观几何形状与PIEZO1介导的钙信号之间的直接相关性。我们发现,微量移液管尖端角度和物理收缩的增加导致F-肌动蛋白的显着重组,积聚在抽吸的细胞颈部,并随后放大细胞圆顶处的张力应力以诱导更多的PIEZO1活性。F-肌动蛋白网络的破坏或其流动性的抑制导致PIEZO1介导的钙内流的显着下降,强调其在几何约束下的细胞机械传感中的关键作用。
    The microgeometry of the cellular microenvironment profoundly impacts cellular behaviors, yet the link between it and the ubiquitously expressed mechanosensitive ion channel PIEZO1 remains unclear. Herein, we describe a fluorescent micropipette aspiration assay that allows for simultaneous visualization of intracellular calcium dynamics and cytoskeletal architecture in real-time, under varied micropipette geometries. By integrating elastic shell finite element analysis with fluorescent lifetime imaging microscopy and employing PIEZO1-specific transgenic red blood cells and HEK cell lines, we demonstrate a direct correlation between the microscale geometry of aspiration and PIEZO1-mediated calcium signaling. We reveal that increased micropipette tip angles and physical constrictions lead to a significant reorganization of F-actin, accumulation at the aspirated cell neck, and subsequently amplify the tension stress at the dome of the cell to induce more PIEZO1\'s activity. Disruption of the F-actin network or inhibition of its mobility leads to a notable decline in PIEZO1 mediated calcium influx, underscoring its critical role in cellular mechanosensing amidst geometrical constraints.
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  • 文章类型: Journal Article
    慢性周围神经性疼痛(PNP)是一种使人衰弱的病症,与许多类型的损伤/疾病相关,包括糖尿病。长期糖尿病患者发展为糖尿病PNP(DPNP),对目前可用的药物有弹性。DPNP的潜在分子机制仍然是虚幻的,但与各种类型慢性疼痛发病机制有关的Kv7通道可能参与其中。的确,采用链脲佐菌素(STZ)DPNP大鼠模型,我们之前已经证明Kv7激活及其非选择性激活剂瑞替加滨可减弱神经性疼痛行为,提示这些通道与DPNP发病机制有关.这里,我们评估,在同一个STZ模型中,更有效和更有选择性的Kv7通道开放剂氟吡汀和ML213是否减弱STZ诱导的疼痛超敏反应。
    使用雄性SpragueDawley大鼠(250-300g)。STZ模型包括单次注射STZ(60mg/kg,i.p.)。使用动态足底麻醉仪和Hargreaves镇痛仪进行机械和热痛敏感性的行为测试,分别。
    STZ大鼠表现出机械和热超敏反应的行为体征,这表明平均爪退缩阈值(PWT)和平均爪退缩潜伏期(PWL)显着降低,分别,在STZ治疗后35天。单次注射氟吡汀(10mg/kg,i.p.)和ML213(5mg/kg,i.p.)对STZ大鼠(STZ治疗后35天)引起平均PWT显着增加,但不是PWL,指示机械衰减,但不是热过敏。氟吡汀和ML213均与阳性对照加巴喷丁(10/kg,i.p.),Kv7通道特异性阻断剂XE991(3mg/kg,i.p.)。
    研究结果表明,Kv7通道参与了与DPNP相关的机械而不是热超敏反应的机制,并且它们的激活可能被证明在缓解DPNP症状方面是有效的。
    UNASSIGNED: Chronic peripheral neuropathic pain (PNP) is a debilitating condition that is associated with many types of injury/diseases, including diabetes mellitus. Patients with longstanding diabetes develop diabetic PNP (DPNP), which is resilient to currently available drugs. The underlying molecular mechanisms of DPNP are still illusive, but Kv7 channels that have been implicated in the pathogenesis of various types of chronic pain are likely to be involved. Indeed, using the streptozotocin (STZ) rat model of DPNP, we have previously shown that Kv7 activation with their non-selective activator retigabine attenuated neuropathic pain behavior suggesting that these channels are implicated in DPNP pathogenesis. Here, we evaluated, in the same STZ model, whether the more potent and more selective Kv7 channel openers flupirtine and ML213 attenuate STZ-induced pain hypersensitivity.
    UNASSIGNED: Male Sprague Dawley rats (250-300 g) were used. The STZ model involved a single injection of STZ (60 mg/kg, i.p.). Behavioral testing for mechanical and heat pain sensitivity was performed using a dynamic plantar aesthesiometer and Hargreaves analgesiometer, respectively.
    UNASSIGNED: STZ rats exhibited behavioral signs of mechanical and heat hypersensitivity as indicated by significant decreases in the mean paw withdrawal threshold (PWT) and mean paw withdrawal latency (PWL), respectively, at 35 days post-STZ treatment. Single injections of flupirtine (10 mg/kg, i.p.) and ML213 (5 mg/kg, i.p.) to STZ rats (35-days after STZ treatment) caused significant increases in the mean PWT, but not PWL, indicating attenuation of mechanical, but not heat hypersensitivity. Both flupirtine and ML213 were as effective as the positive control gabapentin (10/kg, i.p.), and their anti-allodynic effects were prevented by the Kv7 channel-specific blocker XE991 (3 mg/kg, i.p.).
    UNASSIGNED: The findings suggest that Kv7 channels are involved in the mechanisms of mechanical but not heat hypersensitivity associated with DPNP, and that their activation may prove to be effective in alleviating DPNP symptoms.
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  • 文章类型: Journal Article
    作为各种储能转换装置的关键部件,质子交换膜(PEM)已经引起了人们的极大兴趣。然而,它们的进一步发展受到全氟磺酸聚合物的高成本和酸掺杂的非氟化聚合物的差的稳定性的限制。最近,通过杂交多金属氧酸盐(POM)开发了一组新的PEM,一组超酸性亚纳米级金属氧化物簇,与聚合物。POM可以同时作为质子海绵和稳定剂,它们与聚合物的络合可以进一步提高聚合物的机械性能和加工性能。大量的工作集中在研究POM与各种聚合物的超分子络合或共价接枝,以优化PEM的成本,机械性能和稳定性。这个概念总结了这一新兴领域的最新进展,并概述了使用POM-聚合物混合材料作为PEM的设计策略和应用前景。
    As the key component of various energy storage and conversion devices, proton exchange membranes (PEMs) have been attracting significant interest. However, their further development is limited by the high cost of perfluorosulfonic acid polymers and the poor stability of acid-dopped non-fluorinated polymers. Recently, a new group of PEMs has been developed by hybridizing polyoxometalates (POMs), a group of super acidic sub-nanoscale metal oxide clusters, with polymers. POMs can serve simultaneously as both proton sponges and stabilizing agents, and their complexation with polymers can further improve polymers\' mechanical performance and processability. Enormous efforts have been focused on studying supramolecular complexation or covalent grafting of POMs with various polymers to optimize PEMs in terms of cost, mechanical properties and stabilities. This concept summarizes recent advances in this emerging field and outlines the design strategies and application perspectives employed for using POM-polymer hybrid materials as PEMs.
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  • 文章类型: Journal Article
    伤口愈合涉及身体,化学和免疫过程。瞬时受体电位(TRP)和其他离子通道与表皮再上皮化有关。跨离子通道的离子运动可以诱导跨膜电位,从而导致跨上皮电位(TEP)变化。TEP存在于病变周围的表皮中,减少并诱导内源性直流电产生上皮电场(EF),这可能与伤口上皮再形成有关。TRP通道主要在伤口愈合的炎症阶段参与免疫细胞的激活。该研究的目的是在小鼠体内实验中回顾离子通道参与伤口愈合的机制(小鼠,大鼠)以及如何影响这一过程。这篇评论使用了过去一年和今年迄今为止(2023年1月1日至12月31日3000)在科学期刊上发表的最新结果,以包括新闻中的文章。某些类型的TRP频道,如TRPV1、TRPV3和TRPA1,在免疫细胞中表达,并可被炎症介质激活。使用TRPV1,TRPV4和TRPA1通道的激动剂或通过用拮抗剂抑制,反义寡核苷酸或敲低TRPV3和TRPM8通道。
    Wound healing involves physical, chemical and immunological processes. Transient receptor potential (TRP) and other ion channels are implicated in epidermal re-epithelization. Ion movement across ion channels can induce transmembrane potential that leads to transepithelial potential (TEP) changes. TEP is present in epidermis surrounding the lesion decreases and induces an endogenous direct current generating an epithelial electric field (EF) that could be implicated in wound re-epithelialization. TRP channels are involved in the activation of immune cells during mainly the inflammatory phase of wound healing. The aim of the study was to review the mechanisms of ion channel involvement in wound healing in in vivo experiments in murine (mice, rats) and how can this process be influenced. This review used the latest results published in scientific journals over the last year and this year to date (1 January 2023-31 December 3000) in order to include the in-press articles. Some types of TRP channels, such as TRPV1, TRPV3 and TRPA1, are expressed in immune cells and can be activated by inflammatory mediators. The most beneficial effects in wound healing are produced using agonists of TRPV1, TRPV4 and TRPA1 channels or by inhibiting with antagonists, antisense oligonucleotides or knocking down TRPV3 and TRPM8 channels.
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  • 文章类型: Journal Article
    Krause的小体是典型的皮肤粘液上皮,像唇瓣或阴蒂,并且与快速适应参与轻柔触摸或振动的低阈值机械感受器有关。PIEZO1和PIEZO2是跨膜机械门控蛋白,其形成哺乳动物细胞中机械敏感性所需的阳离子离子通道的一部分。他们参与了躯体敏感性,尤其是在不同的触摸品质中,还有疼痛和本体感受。在本研究中,采用免疫组织化学和免疫荧光分析人阴蒂Krause小体中PIEZO1和PIEZO2的发生和细胞定位。在轴突和末端神经胶质细胞的Krause小体中均检测到PIEZO1和PIEZO2。本文首次报道了克劳斯小体末端神经胶质细胞中PIEZOs的存在。根据PIEZO1和PIEZO2的分布,可以假设它们可能参与机械刺激,性行为,和性快感。
    Krause\'s corpuscles are typical of cutaneous mucous epithelia, like the lip vermillion or the glans clitoridis, and are associated with rapidly adapting low-threshold mechanoreceptors involved in gentle touch or vibration. PIEZO1 and PIEZO2 are transmembrane mechano-gated proteins that form a part of the cationic ion channels required for mechanosensitivity in mammalian cells. They are involved in somatosensitivity, especially in the different qualities of touch, but also in pain and proprioception. In the present study, immunohistochemistry and immunofluorescence were used to analyze the occurrence and cellular location of PIEZO1 and PIEZO2 in human clitoral Krause\'s corpuscles. Both PIEZO1 and PIEZO2 were detected in Krause\'s corpuscles in both the axon and the terminal glial cells. The presence of PIEZOs in the terminal glial cells of Kraus\'s corpuscles is reported here for the first time. Based on the distribution of PIEZO1 and PIEZO2, it may be assumed they could be involved in mechanical stimuli, sexual behavior, and sexual pleasure.
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  • 文章类型: Journal Article
    溶酶体是高度动态的细胞器,可通过整合多种代谢途径来维持细胞稳态并调节基本的细胞过程。溶酶体离子通道如TRPML1-3、TPC1/2、ClC6/7、CLN7和TMEM175介导Ca2+的流动,Cl-,Na+,H+,和K+穿过溶酶体膜以响应渗透刺激,营养依赖性信号,和细胞压力。这些离子通道作为细胞信号的关键传感器,对于溶酶体生物发生的调节是必不可少的,运动性,膜接触位点的形成,和溶酶体稳态。在病理生理学方面,这些通道基因的遗传变异与溶酶体贮积病的发展有关,神经退行性疾病,炎症,和癌症。这篇综述旨在讨论目前对这些离子通道在中枢神经系统中的作用的理解,并评估它们作为药物靶标的潜力。
    Lysosomes are highly dynamic organelles that maintain cellular homeostasis and regulate fundamental cellular processes by integrating multiple metabolic pathways. Lysosomal ion channels such as TRPML1-3, TPC1/2, ClC6/7, CLN7, and TMEM175 mediate the flux of Ca2+, Cl-, Na+, H+, and K+ across lysosomal membranes in response to osmotic stimulus, nutrient-dependent signals, and cellular stresses. These ion channels serve as the crucial transducers of cell signals and are essential for the regulation of lysosomal biogenesis, motility, membrane contact site formation, and lysosomal homeostasis. In terms of pathophysiology, genetic variations in these channel genes have been associated with the development of lysosomal storage diseases, neurodegenerative diseases, inflammation, and cancer. This review aims to discuss the current understanding of the role of these ion channels in the central nervous system and to assess their potential as drug targets.
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  • 文章类型: Journal Article
    由于暴露于一些最常用的抗癌药物(铂类药物,紫杉烷,长春花生物碱,蛋白酶体抑制剂,沙利度胺),所谓的化疗诱导的周围神经毒性(CIPN)。CIPN可以是持久的,甚至是永久的,这对癌症幸存者的生活质量有害,与由于主要是感觉轴索性多发性神经病/神经病引起的肢体四肢感觉丧失和神经性疼痛等持续性障碍有关。在最先进的技术中,这种情况没有有效的预防/治疗方法。在这种未满足的临床和科学需求的原因中,对致病机制有不完全的了解。离子通道和转运蛋白是中枢和周围神经系统的关键元件,越来越多的文献表明它们可能在CIPN的发展中发挥作用。在这次审查中,我们首先描述这些靶标的生物物理特性,然后报告有关CIPN中离子通道和转运蛋白参与的现有数据,从而为治愈和/或预防CIPN的新方法/可药物靶标铺平道路。
    The peripheral nervous system can encounter alterations due to exposure to some of the most commonly used anticancer drugs (platinum drugs, taxanes, vinca alkaloids, proteasome inhibitors, thalidomide), the so-called chemotherapy-induced peripheral neurotoxicity (CIPN). CIPN can be long-lasting or even permanent, and it is detrimental for the quality of life of cancer survivors, being associated with persistent disturbances such as sensory loss and neuropathic pain at limb extremities due to a mostly sensory axonal polyneuropathy/neuronopathy. In the state of the art, there is no efficacious preventive/curative treatment for this condition. Among the reasons for this unmet clinical and scientific need, there is an uncomplete knowledge of the pathogenetic mechanisms. Ion channels and transporters are pivotal elements in both the central and peripheral nervous system, and there is a growing body of literature suggesting that they might play a role in CIPN development. In this review, we first describe the biophysical properties of these targets and then report existing data for the involvement of ion channels and transporters in CIPN, thus paving the way for new approaches/druggable targets to cure and/or prevent CIPN.
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  • 文章类型: Journal Article
    在心脏的不同区域,动作电位波形由于钠的表达不同而不同,钙,和钾通道。心肌梗死(MI)的特征之一是氧气供需失衡,导致离子失衡。MI之后,K+的调节和表达水平,Ca2+,心肌细胞中的Na+离子通道被改变,影响心律的规律性,导致心肌损伤。心肌成纤维细胞是MI修复进程中的主要效应细胞。心肌成纤维细胞的离子通道在MI的进程中起主要感化。同时,大量的离子通道在免疫细胞中表达,通过调节离子的流入和流出来完成细胞内信号转导,发挥重要作用。离子通道广泛分布于多种细胞中,是药物开发的有吸引力的靶标。本文综述了MI后不同离子通道的变化以及这些离子通道的治疗药物。我们分析了心肌离子通道调节背后的复杂分子机制和离子通道药物治疗的挑战。
    In different areas of the heart, action potential waveforms differ due to differences in the expressions of sodium, calcium, and potassium channels. One of the characteristics of myocardial infarction (MI) is an imbalance in oxygen supply and demand, leading to ion imbalance. After MI, the regulation and expression levels of K+, Ca2+, and Na+ ion channels in cardiomyocytes are altered, which affects the regularity of cardiac rhythm and leads to myocardial injury. Myocardial fibroblasts are the main effector cells in the process of MI repair. The ion channels of myocardial fibroblasts play an important role in the process of MI. At the same time, a large number of ion channels are expressed in immune cells, which play an important role by regulating the in- and outflow of ions to complete intracellular signal transduction. Ion channels are widely distributed in a variety of cells and are attractive targets for drug development. This article reviews the changes in different ion channels after MI and the therapeutic drugs for these channels. We analyze the complex molecular mechanisms behind myocardial ion channel regulation and the challenges in ion channel drug therapy.
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