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No transcriptional evidence for active Nav channels in two classes of cancer cell 在两类癌细胞中没有活性Nav通道的转录证据
IF 3.3 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2019-01-01 DOI: 10.1080/19336950.2019.1644858
Supanida Hompoonsup, D. Chambers, P. Doherty, Gareth Williams
ABSTRACT Voltage-gated sodium channel (Nav) expression in non-excitable cells has raised questions regarding their non-canonical roles. Interestingly, a growing body of evidence also points towards the prevalence of aberrant Nav expression in malignant tumors, potentially opening a new therapeutic window. In this study, the transcriptional consequences of channel inhibition were investigated in non-small cell lung carcinoma H460 and neuroblastoma SH-SYSY cell lines, that both express Nav1.7. Channel activity was blocked by the application of both selective, ProTx-II, and non-selective, tetrodotoxin, inhibitors. Global gene expression profiling did not point to any statistically significant inhibition-associated perturbation of the transcriptome. A small subset of genes that showed relatively consistent changes across multiple treatments were further assayed in the context of a multiplex bead expression array which failed to recapitulate the changes seen in the global array. We conclude that there is no robust transcriptional signature associated with the inhibition of two sodium channel expressing cancer cell lines and consequently sodium channel inhibition will not lend itself to therapeutic approaches such as transcription-based drug repurposing.
电压门控钠通道(Nav)在不可兴奋细胞中的表达引起了人们对其非规范作用的质疑。有趣的是,越来越多的证据也指向了恶性肿瘤中Nav异常表达的普遍存在,这可能会打开一个新的治疗窗口。本研究在表达Nav1.7的非小细胞肺癌H460和神经母细胞瘤SH-SYSY细胞系中研究了通道抑制的转录后果。通道活性被选择性的ProTx-II和非选择性的河豚毒素抑制剂阻断。全球基因表达谱没有指出任何统计学上显著的抑制相关的转录组扰动。在多重头表达阵列的背景下,进一步分析了在多种处理中表现出相对一致变化的一小部分基因,该基因未能概括全局阵列中所见的变化。我们得出的结论是,没有强大的转录特征与抑制两种表达钠通道的癌细胞系相关,因此钠通道抑制将不适合用于治疗方法,如基于转录的药物再利用。
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引用次数: 1
The influence of membrane bilayer thickness on KcsA channel activity 膜双层厚度对KcsA通道活性的影响
IF 3.3 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2019-01-01 DOI: 10.1080/19336950.2019.1676367
K. Callahan, Benoit Mondou, Louis J. Sasseville, J. Schwartz, N. D'Avanzo
ABSTRACT Atomic resolution structures have provided significant insight into the gating and permeation mechanisms of various ion channels, including potassium channels. However, ion channels may also be regulated by numerous factors, including the physiochemical properties of the membrane in which they are embedded. For example, the matching of the bilayer’s hydrophobic region to the hydrophobic external surface of the ion channel is thought to minimize the energetic penalty needed to solvate hydrophobic residues or exposed lipid tails. To understand the molecular basis of such regulation by hydrophobic matching requires examining channels in the presence of the lipid membrane. Here we examine the role of hydrophobic matching in regulating the activity of the model potassium channel, KcsA. 86Rb+ influx assays and single-channel recordings indicate that the non-inactivating E71A KcsA channel is most active in thin bilayers (
原子分辨率结构为各种离子通道(包括钾离子通道)的门控和渗透机制提供了重要的见解。然而,离子通道也可能受到许多因素的调节,包括它们所嵌入的膜的物理化学性质。例如,双分子层的疏水区域与离子通道的疏水外表面的匹配被认为可以最大限度地减少溶剂化疏水残基或暴露的脂质尾部所需的能量惩罚。要了解这种疏水匹配调节的分子基础,需要在脂质膜存在的情况下检查通道。在这里,我们研究了疏水匹配在调节模式钾通道KcsA活性中的作用。86Rb+内流试验和单通道记录表明,非失活的E71A KcsA通道在薄双层中最活跃(
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引用次数: 12
Acid-sensing ion channels mediate the degeneration of intervertebral disc via various pathways—A systematic review 酸感离子通道通过多种途径介导椎间盘退变-一项系统综述
IF 3.3 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2019-01-01 DOI: 10.1080/19336950.2019.1664038
Yingjun Guo, Y. Meng, Hao Liu, Beiyu Wang, C. Ding, X. Rong, Yi Yang, Y. Hong
ABSTRACT To elucidate the pathological significance of acid-sensing ion channels (ASICs) in intervertebral disc degeneration (IVDD), the database of Medline, Web of Science, and EmBase were carefully screened. Search terms used in each database varied slightly to optimize results. Data relating to the correlation between ASICs and IVDD was systematically collected and integrated into the review. 11 basic science studies, containing the related information, were finally identified for inclusion. Intervertebral disc degeneration (IVDD) is a common disease in middle-aged and elderly people, which has a great impact on patients’ quality of life. Many research teams have attempted to elucidate the pathogenesis of this degenerative disease, and have made considerable progress. Acid-sensing ion channels (ASICs) were once reported to be able to regulate the apoptosis process of chondrocytes in joint cartilage, which has been transplanted into the IVDD-related research. ASIC1a functions as the mediator for cells in nucleus pulposus (NP) and endplate (EP), with whose activation the apoptosis process would be accelerated. Moreover, ASIC1a’s activation could also regulate the anabolism in chondrocytes of EP, facilitating the degeneration. ASIC3 would only promote the degeneration in NP, possibly via its pro-inflammatory effect. The distribution of ASICs in NP, EP, annulus fibrosus, and the particular functions of ASIC1a and ASIC3 remind us about the pathological significance of ASICs in IVDD, which could be a promising therapeutic target in future treatment for IVDD.
为了阐明酸感离子通道(asic)在椎间盘退变(IVDD)中的病理意义,我们对Medline、Web of Science和EmBase数据库进行了仔细筛选。为了优化结果,每个数据库中使用的搜索词略有不同。有关asic和IVDD之间相关性的数据被系统地收集并整合到综述中。包含相关资料的11项基础科学研究最终确定纳入。椎间盘退变(IVDD)是中老年人的常见病,对患者的生活质量影响很大。许多研究小组试图阐明这种退行性疾病的发病机制,并取得了相当大的进展。酸感离子通道(Acid-sensing ion channels, asic)曾被报道能够调控关节软骨中软骨细胞的凋亡过程,并被移植到ivdd的相关研究中。ASIC1a作为髓核(NP)和终板(EP)细胞的介质,其激活会加速细胞凋亡过程。此外,ASIC1a的激活还可以调节EP软骨细胞的合成代谢,促进EP的变性。ASIC3仅促进NP的变性,可能是通过其促炎作用。asic在NP、EP、纤维环中的分布以及ASIC1a和ASIC3的特殊功能提醒我们asic在IVDD中的病理意义,这可能是未来治疗IVDD的一个有希望的治疗靶点。
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引用次数: 7
Anterograde trafficking signals in GABAA subunits are required for functional expression GABAA亚基的顺行转运信号是功能表达所必需的
IF 3.3 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2019-01-01 DOI: 10.1080/19336950.2019.1676368
Jessica L. Nuwer, M. Fleck
ABSTRACT Pentameric GABAA receptors are composed from 19 possible subunits. The GABAA β subunit is unique because the β1 and β3 subunits can assemble and traffic to the cell surface as homomers, whereas most of the other subunits, including β2, are heteromers. The intracellular domain (ICD) of the GABAA subunits has been implicated in targeting and clustering GABAA receptors at the plasma membrane. Here, we sought to test whether and how the ICD is involved in functional expression of the β3 subunit. Since θ is the most homologous to β but does not form homomers, we created two reciprocal chimeric subunits, swapping the ICD between the β3 and θ subunits, and expressed them in HEK293 cells. Surface expression was detected with immunofluorescence and functional expression was quantified using whole-cell patch-clamp recording with fast perfusion. Results indicate that, unlike β3, neither the β3/θIC nor the θ/β3IC chimera can traffic to the plasma membrane when expressed alone; however, when expressed in combination with either wild-type α3 or β3, the β3/θIC chimera was functionally expressed. This suggests that the ICD of α3 and β3 each contain essential anterograde trafficking signals that are required to overcome ER retention of assembled GABAA homo- or heteropentamers.
五聚体GABAA受体由19个可能的亚基组成。GABAA β亚基是独特的,因为β1和β3亚基可以作为同聚体组装并运输到细胞表面,而大多数其他亚基,包括β2,都是异聚体。GABAA亚基的胞内结构域(ICD)与GABAA受体在质膜上的靶向和聚集有关。在这里,我们试图测试ICD是否以及如何参与β3亚基的功能表达。由于θ与β最同源,但不形成同源体,我们创建了两个相互嵌合的亚基,将ICD交换在β3和θ亚基之间,并在HEK293细胞中表达。免疫荧光法检测表面表达,快速灌注全细胞膜片钳记录功能表达。结果表明,与β3不同,β3/θ ic和θ/β3IC嵌合体在单独表达时均不能转运到质膜;然而,当与野生型α3或β3结合表达时,β3/θIC嵌合体都能得到功能性表达。这表明α3和β3的ICD都包含必要的逆行运输信号,这些信号是克服组装的GABAA同源或异聚体的内质网保留所必需的。
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引用次数: 0
Heteromeric TRPV4/TRPC1 channels mediate calcium-sensing receptor-induced relaxations and nitric oxide production in mesenteric arteries: comparative study using wild-type and TRPC1−/- mice 异质TRPV4/TRPC1通道介导钙敏感受体诱导的系膜动脉松弛和一氧化氮产生:野生型和TRPC1−/-小鼠的比较研究
IF 3.3 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2019-01-01 DOI: 10.1080/19336950.2019.1673131
H. Greenberg, S. R. Carlton-Carew, A. Zargaran, K. S. Jahan, L. Birnbaumer, A. Albert
ABSTRACT We have previously provided pharmacological evidence that stimulation of calcium-sensing receptors (CaSR) induces endothelium-dependent relaxations of rabbit mesenteric arteries through activation of heteromeric TRPV4/TRPC1 channels and nitric oxide (NO) production. The present study further investigates the role of heteromeric TRPV4/TRPC1 channels in these CaSR-induced vascular responses by comparing responses in mesenteric arteries from wild-type (WT) and TRPC1-/- mice. In WT mice, stimulation of CaSR induced endothelium-dependent relaxations of pre-contracted tone and NO generation in endothelial cells (ECs), which were inhibited by the TRPV4 channel blocker RN1734 and the TRPC1 blocking antibody T1E3. In addition, TRPV4 and TRPC1 proteins were colocalised at, or close to, the plasma membrane of endothelial cells (ECs) from WT mice. In contrast, in TRPC1-/- mice, CaSR-mediated vasorelaxations and NO generation were greatly reduced, unaffected by T1E3, but blocked by RN1734. In addition, the TRPV4 agonist GSK1016790A (GSK) induced endothelium-dependent vasorelaxations which were blocked by RN1734 and T1E3 in WT mice, but only by RN1734 in TRPC1-/- mice. Moreover, GSK activated cation channel activity with a 6pS conductance in WT ECs but with a 52 pS conductance in TRPC1-/- ECs. These results indicate that stimulation of CaSR activates heteromeric TRPV4/TRPC1 channels and NO production in ECs, which are responsible for endothelium-dependent vasorelaxations. This study also suggests that heteromeric TRPV4-TRPC1 channels may form the predominant TRPV4-containing channels in mouse mesenteric artery ECs. Together, our data further implicates CaSR-induced pathways and heteromeric TRPV4/TRPC1 channels in the regulation of vascular tone.
我们之前提供的药理学证据表明,刺激钙敏感受体(CaSR)通过激活异质TRPV4/TRPC1通道和一氧化氮(NO)的产生,诱导兔肠动脉内皮依赖性松弛。本研究通过比较野生型(WT)和TRPC1-/-小鼠肠系膜动脉的反应,进一步探讨了异质TRPV4/TRPC1通道在这些casr诱导的血管反应中的作用。在WT小鼠中,CaSR刺激诱导内皮细胞(ECs)内皮依赖性预收缩张力松弛和NO生成,这些被TRPV4通道阻断剂RN1734和TRPC1阻断抗体T1E3抑制。此外,TRPV4和TRPC1蛋白共定位于或靠近WT小鼠内皮细胞(ECs)的质膜。相比之下,在TRPC1-/-小鼠中,casr介导的血管松弛和NO生成大大减少,不受T1E3的影响,但被RN1734阻断。此外,TRPV4激动剂GSK1016790A (GSK)诱导的内皮依赖性血管松弛在WT小鼠中被RN1734和T1E3阻断,而在TRPC1-/-小鼠中仅被RN1734阻断。此外,GSK激活的阳离子通道活性在WT ec中为6pS电导,而在TRPC1-/- ec中为52 pS电导。这些结果表明,刺激CaSR激活内皮细胞中异质TRPV4/TRPC1通道和NO的产生,这些通道负责内皮依赖性血管松弛。本研究还提示异质TRPV4-TRPC1通道可能在小鼠肠系膜动脉内皮细胞中形成主要的含trpv4通道。总之,我们的数据进一步暗示了casr诱导通路和异质TRPV4/TRPC1通道在血管张力调节中的作用。
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引用次数: 9
Voltage vs. Ligand I: Structural basis of the intrinsic flexibility of S3 segment and its significance in ion channel activation 电压与配体I: S3节段固有柔韧性的结构基础及其在离子通道激活中的意义
IF 3.3 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2019-01-01 DOI: 10.1080/19336950.2019.1674242
Daniel Balleza, Mario E Rosas, S. Romero-Romero
ABSTRACT We systematically predict the internal flexibility of the S3 segment, one of the most mobile elements in the voltage-sensor domain. By analyzing the primary amino acid sequences of V-sensor containing proteins, including Hv1, TPC channels and the voltage-sensing phosphatases, we established correlations between the local flexibility and modes of activation for different members of the VGIC superfamily. Taking advantage of the structural information available, we also assessed structural aspects to understand the role played by the flexibility of S3 during the gating of the pore. We found that S3 flexibility is mainly determined by two specific regions: (1) a short NxxD motif in the N-half portion of the helix (S3a), and (2) a short sequence at the beginning of the so-called paddle motif where the segment has a kink that, in some cases, divide S3 into two distinct helices (S3a and S3b). A good correlation between the flexibility of S3 and the reported sensitivity to temperature and mechanical stretch was found. Thus, if the channel exhibits high sensitivity to heat or membrane stretch, local S3 flexibility is low. On the other hand, high flexibility of S3 is preferentially associated to channels showing poor heat and mechanical sensitivities. In contrast, we did not find any apparent correlation between S3 flexibility and voltage or ligand dependence. Overall, our results provide valuable insights into the dynamics of channel-gating and its modulation.
我们系统地预测了S3段的内部灵活性,S3段是电压传感器领域中最具移动性的元件之一。通过分析V-sensor蛋白(包括Hv1、TPC通道和电压感应磷酸酶)的一级氨基酸序列,我们建立了VGIC超家族不同成员的局部柔韧性与激活模式之间的相关性。利用现有的结构信息,我们还对结构方面进行了评估,以了解S3的灵活性在孔的门控过程中所起的作用。我们发现S3的灵活性主要由两个特定区域决定:(1)螺旋n -半部分的短NxxD基序(S3a),以及(2)所谓的桨基序开始的短序列,该片段具有扭结,在某些情况下,将S3分成两个不同的螺旋(S3a和S3b)。发现S3的柔韧性与报告的温度敏感性和机械拉伸之间存在良好的相关性。因此,如果通道对热或膜拉伸表现出高敏感性,则局部S3柔韧性较低。另一方面,S3的高灵活性优先与表现出较差的热和机械敏感性的通道相关。相反,我们没有发现S3柔韧性与电压或配体依赖性之间有任何明显的相关性。总的来说,我们的结果为通道门控及其调制的动力学提供了有价值的见解。
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引用次数: 9
Silencing of KCNA1 suppresses the cervical cancer development via mitochondria damage KCNA1的沉默通过线粒体损伤抑制宫颈癌的发展
IF 3.3 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2019-01-01 DOI: 10.1080/19336950.2019.1648627
Li Liu, Yumei Chen, Qingyuan Zhang, Changzhong Li
ABSTRACT Voltage-gated potassium channel subfamily A member 1 (KCNA1/Kv1.1) is an important component of type A potassium channels, which has been found to be involved in various tumors. This study aimed to identify the role of KCNA1 in cervical cancer and explore the related mechanism. The levels of KCNA1 in cervical cancer tissues and cell lines were examined by Western blot and qPCR. Cell proliferation and invasion were assessed by CCK-8 and transwell assays, respectively. Protein levels of Hedgehog (Hhg), Wnt and Notch were detected by Western blot. The mitochondrial capacity was examined by immunostaining with MitoTracker Red CMXRos. KCNA1 was highly expressed in cervical cancer tissues and cell lines, and correlated with poor prognosis. In addition, depletion of KCNA1 suppressed growth, proliferation, migration and invasion of HeLa cells. Moreover, KCNA1 could regulate the Hhg, Wnt and Notch signaling pathways and cause mitochondrial dysfunction. The present study has demonstrated that KCNA1 is an oncogene excessively expressed in cervical cancer, and promotes tumor progression by regulating the Hhg, Wnt and Notch signaling pathways and the mitochondrial capacity. Therefore, our results provide a theoretical basis for the discovery of novel clinical treatment against cervical cancer.
电压门控钾通道亚家族A成员1 (KCNA1/Kv1.1)是A型钾通道的重要组成部分,已发现其参与多种肿瘤。本研究旨在确定KCNA1在宫颈癌中的作用并探讨其相关机制。Western blot和qPCR检测宫颈癌组织和细胞系中KCNA1的表达水平。分别用CCK-8和transwell检测细胞增殖和侵袭。Western blot检测Hedgehog (Hhg)、Wnt、Notch蛋白水平。用MitoTracker Red CMXRos免疫染色检测线粒体容量。KCNA1在宫颈癌组织和细胞系中高表达,与预后不良相关。此外,KCNA1的缺失抑制HeLa细胞的生长、增殖、迁移和侵袭。此外,KCNA1还能调控Hhg、Wnt和Notch信号通路,导致线粒体功能障碍。本研究表明KCNA1是宫颈癌中过度表达的致癌基因,通过调控Hhg、Wnt、Notch信号通路及线粒体容量促进肿瘤进展。因此,我们的研究结果为发现新的宫颈癌临床治疗方法提供了理论依据。
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引用次数: 17
Evaluation of edonerpic maleate as a CRMP2 inhibitor for pain relief 马来酸酯作为CRMP2抑制剂缓解疼痛的评价
IF 3.3 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2019-01-01 DOI: 10.1080/19336950.2019.1684608
Aubin Moutal, Zhiming Shan, Victor G. Miranda, L. François-Moutal, Cynthia L Madura, M. Khanna, R. Khanna
ABSTRACT We have previously reported that the microtubule-associated collapsin response mediator protein 2 (CRMP2) is necessary for the expression of chronic pain. CRMP2 achieves this control of nociceptive signaling by virtue of its ability to regulate voltage-gated calcium and sodium channels. To date, however, no drugs exist that target CRMP2. Recently, the small molecule edonerpic maleate (1 -{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}azetidin-3-ol maleate), a candidate therapeutic for Alzheimer’s disease was reported to be a novel CRMP2 binding compound with the potential to decrease its phosphorylation level in cortical tissues in vivo. Here we sought to determine the mechanism of action of edonerpic maleate and test its possible effect in a rodent model of chronic pain. We observed: (i) no binding between human CRMP2 and edonerpic maleate; (ii) edonerpic maleate had no effect on CRMP2 expression and phosphorylation in dorsal root ganglion (DRG) neurons; (iii) edonerpic maleate-decreased calcium but increased sodium current density in DRG neurons; and (iv) edonerpic maleate was ineffective in reversing post-surgical allodynia in male and female mice. Thus, while CRMP2 inhibiting compounds remain a viable strategy for developing new mechanism-based pain inhibitors, edonerpic maleate is an unlikely candidate.
我们之前报道过微管相关的坍缩反应介质蛋白2 (CRMP2)在慢性疼痛的表达中是必需的。CRMP2通过调节电压门控钙和钠通道的能力来实现对伤害性信号的控制。然而,到目前为止,还没有针对CRMP2的药物。最近,小分子edonerpic maleate(1-{3-[2-(1-苯并噻吩-5-基)乙氧基]丙基}azetitin -3-ol maleate)作为阿尔茨海默病的候选治疗药物被报道为一种新的CRMP2结合化合物,具有降低体内皮质组织中CRMP2磷酸化水平的潜力。在这里,我们试图确定的作用机制,并测试其可能的作用在啮齿动物慢性疼痛模型。我们观察到:(i)人类CRMP2与edonerpic马来酸之间没有结合;(ii)马来酸edonerpic对背根神经节(DRG)神经元中CRMP2的表达和磷酸化没有影响;(iii) edoneric malate - DRG神经元钙电流减少,但钠电流密度增加;(4)戊酸乙酯对雌雄小鼠术后异常性痛的逆转无效。因此,虽然CRMP2抑制化合物仍然是开发新的基于机制的疼痛抑制剂的可行策略,但马来酸乙糖酸酯不太可能成为候选药物。
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引用次数: 2
A conserved arginine/lysine-based motif promotes ER export of KCNE1 and KCNE2 to regulate KCNQ1 channel activity 一个保守的精氨酸/赖氨酸基序促进KCNE1和KCNE2的内质网输出以调节KCNQ1通道活性
IF 3.3 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2019-01-01 DOI: 10.1080/19336950.2019.1685626
Bin Hu, Wenping Zeng, Xia Li, Umar Al-Sheikh, San-You Chen, Jiuping Ding
ABSTRACT KCNE β-subunits play critical roles in modulating cardiac voltage-gated potassium channels. Among them, KCNE1 associates with KCNQ1 channel to confer a slow-activated IKs current, while KCNE2 functions as a dominant negative modulator to suppress the current amplitude of KCNQ1. Any anomaly in these channels will lead to serious myocardial diseases, such as the long QT syndrome (LQTS). Trafficking defects of KCNE1 have been reported to account for the pathogenesis of LQT5. However, the molecular mechanisms underlying KCNE forward trafficking remain elusive. Here, we describe an arginine/lysine-based motif ([R/K](S)[R/K][R/K]) in the proximal C-terminus regulating the endoplasmic reticulum (ER) export of KCNE1 and KCNE2 in HEK293 cells. Notably, this motif is highly conserved in the KCNE family. Our results indicate that the forward trafficking of KCNE2 controlled by the motif (KSKR) is essential for suppressing the cell surface expression and current amplitude of KCNQ1. Unlike KCNE2, the motif (RSKK) in KCNE1 plays important roles in modulating the gating of KCNQ1 in addition to mediating the ER export of KCNE1. Furthermore, truncations of the C-terminus did not reduce the apparent affinity of KCNE2 for KCNQ1, demonstrating that the rigid C-terminus of KCNE2 may not physically interact with KCNQ1. In contrast, the KCNE1 C-terminus is critical for its interaction with KCNQ1. These results contribute to the understanding of the mechanisms of KCNE1 and KCNE2 membrane targeting and how they coassemble with KCNQ1 to regulate the channels activity.
KCNE β-亚基在调节心脏电压门控钾通道中起关键作用。其中,KCNE1与KCNQ1通道相关联,赋予慢激活的IKs电流,而KCNE2作为主要负调制器抑制KCNQ1的电流幅度。这些通道的任何异常都会导致严重的心肌疾病,如长QT综合征(LQTS)。据报道,KCNE1的转运缺陷解释了LQT5的发病机制。然而,KCNE向前贩运的分子机制仍然难以捉摸。在这里,我们描述了一个基于精氨酸/赖氨酸的基序([R/K](S)[R/K][R/K])在HEK293细胞近端c端调节内质网(ER)输出KCNE1和KCNE2。值得注意的是,这个基序在KCNE家族中是高度保守的。我们的研究结果表明,由基序(KSKR)控制的KCNE2的正向转运对于抑制KCNQ1的细胞表面表达和电流幅度是必不可少的。与KCNE2不同,KCNE1中的基序(RSKK)除了介导KCNE1的内质网输出外,还在KCNQ1的门控调节中起重要作用。此外,c末端的截断并没有降低KCNE2对KCNQ1的表观亲和力,这表明KCNE2的刚性c末端可能不会与KCNQ1发生物理相互作用。相反,KCNE1的c端对其与KCNQ1的相互作用至关重要。这些结果有助于理解KCNE1和KCNE2膜靶向的机制,以及它们如何与KCNQ1一起调节通道活性。
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引用次数: 4
Elementary calcium signaling in arterial smooth muscle 动脉平滑肌中的基本钙信号
IF 3.3 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2019-01-01 DOI: 10.1080/19336950.2019.1688910
Gang Fan, Yingqiu Cui, M. Gollasch, M. Kassmann
ABSTRACT Vascular smooth muscle cells (VSMCs) of small peripheral arteries contribute to blood pressure control by adapting their contractile state. These adaptations depend on the VSMC cytosolic Ca2+ concentration, regulated by complex local elementary Ca2+ signaling pathways. Ca2+ sparks represent local, transient, rapid calcium release events from a cluster of ryanodine receptors (RyRs) in the sarcoplasmic reticulum. In arterial SMCs, Ca2+ sparks activate nearby calcium-dependent potassium channels, cause membrane hyperpolarization and thus decrease the global intracellular [Ca2+] to oppose vasoconstriction. Arterial SMC Cav1.2 L-type channels regulate intracellular calcium stores content, which in turn modulates calcium efflux through RyRs. Cav3.2 T-type channels contribute to a minor extend to Ca2+ spark generation in certain types of arteries. Their localization within cell membrane caveolae is essential. We summarize present data on local elementary calcium signaling (Ca2+ sparks) in arterial SMCs with focus on RyR isoforms, large-conductance calcium-dependent potassium (BKCa) channels, and cell membrane-bound calcium channels (Cav1.2 and Cav3.2), particularly in caveolar microdomains.
外周小动脉血管平滑肌细胞(VSMCs)通过调节其收缩状态参与血压控制。这些适应依赖于VSMC细胞质Ca2+浓度,由复杂的局部基本Ca2+信号通路调节。钙离子火花代表局部的,短暂的,快速的钙释放事件从肌浆网的一群红嘌呤受体(RyRs)。在动脉SMCs中,Ca2+火花激活附近的钙依赖性钾通道,引起膜超极化,从而降低整体细胞内[Ca2+]以对抗血管收缩。动脉SMC Cav1.2 l型通道调节细胞内钙储存含量,进而调节钙通过RyRs外排。在某些类型的动脉中,Cav3.2 t型通道有助于少量扩展Ca2+火花的产生。它们在细胞膜小泡内的定位至关重要。我们总结了动脉SMCs中局部基本钙信号(Ca2+火花)的现有数据,重点关注RyR亚型,大电导钙依赖性钾(BKCa)通道和细胞膜结合钙通道(Cav1.2和Cav3.2),特别是在腔泡微域。
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引用次数: 22
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