Channels最新文献_第2页

Voltage gated sodium channels in cancer and their potential mechanisms of action. 癌症中的电压门控钠通道及其潜在作用机制。

IF 3.3 3区生物学

Channels Pub Date : 2019-12-01 DOI: 10.1080/19336950.2019.1666455

Madeline Angus, Peter Ruben

{"title":"Voltage gated sodium channels in cancer and their potential mechanisms of action.","authors":"Madeline Angus, Peter Ruben","doi":"10.1080/19336950.2019.1666455","DOIUrl":"10.1080/19336950.2019.1666455","url":null,"abstract":"<p><p>Voltage gated sodium channels (VGSC) are implicated in cancer cell invasion and metastasis. However, the mechanism by which VGSC increase cell invasiveness and probability of metastasis is still unknown. In this review we outline lesser known functions of VGSC outside of action potential propagation, and the current understanding of the effects of VGSC in cancer. Finally, we discuss possible downstream effects of VGSC activation in cancer cells. After extensive review of the literature, the most likely role of VGSC in cancer is in the invadopodia, the leading edge of metastatic cancer cells. Sodium gradients are used to drive many biological processes in the body, and invadopodia may be similar. The function of the sodium hydrogen exchanger (NHE) and sodium calcium exchanger (NCX) are driven by sodium gradients. Voltage gated calcium channels, activated by membrane depolarization, are also capable of becoming activated in response to VGSC activity. Changes to hydrogen ion exchange or calcium handling have functional consequences for invadopodia and would explain the relationship between VGSC expression and invasiveness of cancer cells.</p>","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2019-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76524377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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

Channels Pub Date : 2019-01-01 DOI: 10.1080/19336950.2019.1644858

Supanida Hompoonsup, D. Chambers, P. Doherty, Gareth Williams

{"title":"No transcriptional evidence for active Nav channels in two classes of cancer cell","authors":"Supanida Hompoonsup, D. Chambers, P. Doherty, Gareth Williams","doi":"10.1080/19336950.2019.1644858","DOIUrl":"https://doi.org/10.1080/19336950.2019.1644858","url":null,"abstract":"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.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76673024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

Channels Pub Date : 2019-01-01 DOI: 10.1080/19336950.2019.1676367

K. Callahan, Benoit Mondou, Louis J. Sasseville, J. Schwartz, N. D'Avanzo

{"title":"The influence of membrane bilayer thickness on KcsA channel activity","authors":"K. Callahan, Benoit Mondou, Louis J. Sasseville, J. Schwartz, N. D'Avanzo","doi":"10.1080/19336950.2019.1676367","DOIUrl":"https://doi.org/10.1080/19336950.2019.1676367","url":null,"abstract":"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 (<diC18:1PC). Bilayer thickness affects the open probability of KcsA and not its unitary conductance. Molecular dynamics simulations indicate that the bilayer can sufficiently modify its dimensions to accommodate KcsA channels without major perturbations in the protein helical packing within the nanosecond timescale. Based on experimental results and MD simulations, we present a model in which bilayer thickness influences the stability of the open and closed conformations of the intracellular gate of KcsA, with minimal impact on the stability of the selectivity filter of the non-inactivating mutant, E71A.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79195752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

Channels 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

{"title":"Acid-sensing ion channels mediate the degeneration of intervertebral disc via various pathways—A systematic review","authors":"Yingjun Guo, Y. Meng, Hao Liu, Beiyu Wang, C. Ding, X. Rong, Yi Yang, Y. Hong","doi":"10.1080/19336950.2019.1664038","DOIUrl":"https://doi.org/10.1080/19336950.2019.1664038","url":null,"abstract":"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.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82466843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

Channels Pub Date : 2019-01-01 DOI: 10.1080/19336950.2019.1676368

Jessica L. Nuwer, M. Fleck

{"title":"Anterograde trafficking signals in GABAA subunits are required for functional expression","authors":"Jessica L. Nuwer, M. Fleck","doi":"10.1080/19336950.2019.1676368","DOIUrl":"https://doi.org/10.1080/19336950.2019.1676368","url":null,"abstract":"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.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77021088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

Channels 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

{"title":"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","authors":"H. Greenberg, S. R. Carlton-Carew, A. Zargaran, K. S. Jahan, L. Birnbaumer, A. Albert","doi":"10.1080/19336950.2019.1673131","DOIUrl":"https://doi.org/10.1080/19336950.2019.1673131","url":null,"abstract":"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.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78195583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

Channels Pub Date : 2019-01-01 DOI: 10.1080/19336950.2019.1674242

Daniel Balleza, Mario E Rosas, S. Romero-Romero

{"title":"Voltage vs. Ligand I: Structural basis of the intrinsic flexibility of S3 segment and its significance in ion channel activation","authors":"Daniel Balleza, Mario E Rosas, S. Romero-Romero","doi":"10.1080/19336950.2019.1674242","DOIUrl":"https://doi.org/10.1080/19336950.2019.1674242","url":null,"abstract":"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.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73507205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

Channels Pub Date : 2019-01-01 DOI: 10.1080/19336950.2019.1648627

Li Liu, Yumei Chen, Qingyuan Zhang, Changzhong Li

{"title":"Silencing of KCNA1 suppresses the cervical cancer development via mitochondria damage","authors":"Li Liu, Yumei Chen, Qingyuan Zhang, Changzhong Li","doi":"10.1080/19336950.2019.1648627","DOIUrl":"https://doi.org/10.1080/19336950.2019.1648627","url":null,"abstract":"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.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83128055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

Channels 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

{"title":"Evaluation of edonerpic maleate as a CRMP2 inhibitor for pain relief","authors":"Aubin Moutal, Zhiming Shan, Victor G. Miranda, L. François-Moutal, Cynthia L Madura, M. Khanna, R. Khanna","doi":"10.1080/19336950.2019.1684608","DOIUrl":"https://doi.org/10.1080/19336950.2019.1684608","url":null,"abstract":"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.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87196587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

Channels 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

{"title":"A conserved arginine/lysine-based motif promotes ER export of KCNE1 and KCNE2 to regulate KCNQ1 channel activity","authors":"Bin Hu, Wenping Zeng, Xia Li, Umar Al-Sheikh, San-You Chen, Jiuping Ding","doi":"10.1080/19336950.2019.1685626","DOIUrl":"https://doi.org/10.1080/19336950.2019.1685626","url":null,"abstract":"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.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80548198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4