Channels (Austin, Tex.)最新文献

{"title":"17β-Estradiol activates Cl^- channels via the estrogen receptor α pathway in human thyroid cells.","authors":"Meisheng Yu,&nbsp;Yuan Wei,&nbsp;Yanfang Zheng,&nbsp;Lili Yang,&nbsp;Long Meng,&nbsp;Jiawei Lin,&nbsp;Peisheng Xu,&nbsp;Sanaa Ahmed Nagi Abdu Mahdy,&nbsp;Linyan Zhu,&nbsp;Shuang Peng,&nbsp;Lixin Chen,&nbsp;Liwei Wang","doi":"10.1080/19336950.2021.1957627","DOIUrl":"https://doi.org/10.1080/19336950.2021.1957627","url":null,"abstract":"<p><p>Estradiol regulates thyroid function, and chloride channels are involved in the regulation of thyroid function. However, little is known about the role of chloride channels in the regulation of thyroid functions by estrogen. In this study, the effects of estrogen on chloride channel activities in human thyroid Nthy-ori3-1 cells were therefore investigated using the whole cell patch-clamp technique. The results showed that the extracellular application of 17β-estradiol (E2) activated Cl^- currents, which reversed at a potential close to Cl^- equilibrium potential and showed remarkable outward rectification and an anion permeability of I^- > Br^- > Cl^- > gluconate. The Cl^- currents were inhibited by the chloride channel blockers, NPPB and tamoxifen. Quantitative Real-time PCR results demonstrated that ClC-3 expression was highest in ClC family member in Nthy-ori3-1 cells. The down-regulation of ClC-3 expression by ClC-3 siRNA inhibited E2-induced Cl^- current. The Cl^- current was blocked by the estrogen receptor antagonist, ICI 182780 (fulvestrant). Estrogen receptor alpha (ERα) and not estrogen receptor beta was the protein expressed in Nthy-ori3-1 cells, and the knockdown of ERα expression with ERα siRNA abolished E2-induced Cl^- currents. Estradiol can promote the accumulation of ClC-3 in cell membrane. ERα and ClC-3 proteins were partially co-localized in the cell membrane of Nthy-ori3-1 cells after estrogen exposure. The results suggest that estrogen activates chloride channels via ERα in normal human thyroid cells, and ClC-3 proteins play a pivotal role in the activation of E2-induced Cl^- current.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39341917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transient Receptor Potential channels: A Global Bibliometric analysis From 2012 to 2021.","authors":"Xueping Zhu,&nbsp;Chuanxi Tian,&nbsp;Yan Zhou,&nbsp;Jingjing Shi,&nbsp;Guozhen Yuan,&nbsp;Limei Zhang,&nbsp;Yuchen Jiang,&nbsp;Wenjing Xue,&nbsp;Yihang Du,&nbsp;Yuanhui Hu","doi":"10.1080/19336950.2021.1983100","DOIUrl":"https://doi.org/10.1080/19336950.2021.1983100","url":null,"abstract":"The transient receptor potential (TRP) channels, nonselective ion channels, mediate the fluxes of various types of cations across the cell membrane such as Na+, K+, Mg2+, and Ca2 + . TRPA (Ankyrin), TRPC (Canonical), TRPM (Melastatin), TRPV (Vanilloid), TRPP (Polycystin), and TRPML (Mucolipin) are TRP major families members. These channels play essential roles in diverse physiologic processes, and participate in virtually every sensory modality. TRPs can be activated by chemicals, temperature, stretch/pressure, osmolarity, pH, and so on, and play a major role in the five primary senses, such as vision, taste, hearing, smell, and touch. In recent years, TRP channels are widely studied in the field of nervous, intestinal, renal, urogenital, respiratory, and cardiovascular systems in diverse therapeutic areas including pain and itch, headache, pulmonary function, oncology, neurology, visceral organs, and genetic diseases [1]. Bibliometric analysis has been widely used to calculate the productivity of countries, institutions, authors, and the frequency of keywords to explore research hotspots/frontiers in specific fields [2–4]. In the present study, we performed a bibliometric analysis to systematically evaluate the TRP channels studies from 2012 to 2021 by CiteSpace and VOSviewer to provide researchers with some direction regarding TRP channels research [5,6]. Data source and search","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8667877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39625007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRPV1 channels as a newly identified target for vitamin D.","authors":"Wentong Long, Janyne Johnson, Subha Kalyaanamoorthy, Peter Light","doi":"10.1080/19336950.2021.1905248","DOIUrl":"10.1080/19336950.2021.1905248","url":null,"abstract":"<p><p>Vitamin D is known to elicit many biological effects in diverse tissue types and is thought to act almost exclusively upon its canonical receptor within the nucleus, leading to gene transcriptional changes and the subsequent cellular response. However, not all the observed effects of vitamin D can be attributed to this sole mechanism, and other cellular targets likely exist but remain to be identified. Our recent discovery that vitamin D is a partial agonist of the Transient Receptor Potential Vanilloid family 1 (TRPV1) channel may provide new insights as to how this important vitamin exerts its biological effects either independently or in addition to the nuclear vitamin D receptor. In this review, we discuss the literature surrounding this apparent discrepancy in vitamin D signaling and compare vitamin D with known TRPV1 ligands with respect to their binding to TRPV1. Furthermore, we provide evidence supporting the notion that this novel vitamin D/TRPV1 axis may explain some of the beneficial actions of this vitamin in disease states where TRPV1 expression and vitamin D deficiency are known to overlap. Finally, we discuss whether vitamin D may also act on other members of the TRP family of ion channels.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10296011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of acid-sensing ion channels by protein binding partners.","authors":"Megan M Cullinan,&nbsp;Robert C Klipp,&nbsp;John R Bankston","doi":"10.1080/19336950.2021.1976946","DOIUrl":"https://doi.org/10.1080/19336950.2021.1976946","url":null,"abstract":"<p><p>Acid-sensing ion channels (ASICs) are a family of proton-gated cation channels that contribute to a diverse array of functions including pain sensation, cell death during ischemia, and more broadly to neurotransmission in the central nervous system. There is an increasing interest in understanding the physiological regulatory mechanisms of this family of channels. ASICs have relatively short N- and C-termini, yet a number of proteins have been shown to interact with these domains both <i>in vitro</i> and <i>in vivo</i>. These proteins can impact ASIC gating, localization, cell-surface expression, and regulation. Like all ion channels, it is important to understand the cellular context under which ASICs function in neurons and other cells. Here we will review what is known about a number of these potentially important regulatory molecules.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8555555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39564956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fast desensitization of acetylcholine receptors induced by a spider toxin.","authors":"Na Clara Pan,&nbsp;Tingting Zhang,&nbsp;Shimin Hu,&nbsp;Chunyan Liu,&nbsp;Yuping Wang","doi":"10.1080/19336950.2021.1961459","DOIUrl":"https://doi.org/10.1080/19336950.2021.1961459","url":null,"abstract":"<p><p>Nicotinic acetylcholine receptors (nAChRs) are members of the \"cys-loop\" ligand-gated ion channel superfamily that play important roles in both the peripheral and central system. At the neuromuscular junction, the endplate current is induced by ACh binding and nAChR activation, and then, the current declines to a small steady state, even though ACh is still bound to the receptors. The kinetics of nAChRs with high affinity for ACh but no measurable ion conductance is called desensitization. This adopted desensitization of nAChR channel currents might be an important mechanism for protecting cells against uncontrolled excitation. This study aimed to show that <i>Grammostola spatulata</i> toxin (GsMTx4), which was first purified and characterized from the venom of the tarantula <i>Grammostola spatulata</i> (now genus Phixotricus), can facilitate the desensitization of nAChRs in murine C2C12 myotubes. To examine the details, muscle-type nAChRs, which are expressed heterologously in HEK293T cells, were studied. A single channel current was recorded under the cell-attached configuration, and the channel activity (NP_o) decayed much faster after the addition of GsMTx-4 to the pipette solution. The channel kinetics were further analyzed, and GsMTx-4 affected the channel activity of nAChRs by prolonging the closing time without affecting channel conductance or opening activity. The interaction between nAChRs embedded in the lipid membrane and toxin inserted into the membrane may contribute to the conformational change in the receptor and thus change the channel activity. This new property of GsMTx-4 may lead to a better understanding of the desensitization of ligand-gated channels and disease therapy.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39296654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stabilization of negative activation voltages of Cav1.3 L-Type Ca²⁺-channels by alternative splicing.","authors":"Nadja T Hofer, Alexandra Pinggera, Yuliia V Nikonishyna, Petronel Tuluc, Eva M Fritz, Gerald J Obermair, Jörg Striessnig","doi":"10.1080/19336950.2020.1859260","DOIUrl":"10.1080/19336950.2020.1859260","url":null,"abstract":"<p><p>-->Low voltage-activated Cav1.3 L-type Ca²⁺-channels are key regulators of neuronal excitability controlling neuronal development and different types of learning and memory. Their physiological functions are enabled by their negative activation voltage-range, which allows Cav1.3 to be active at subthreshold voltages. Alternative splicing in the C-terminus of their pore-forming α1-subunits gives rise to C-terminal long (Cav1.3_L) and short (Cav1.3_S) splice variants allowing Cav1.3_S to activate at even more negative voltages than Cav1.3_L. We discovered that inclusion of exons 8b, 11, and 32 in Cav1.3_S further shifts activation (-3 to -4 mV) and inactivation (-4 to -6 mV) to more negative voltages as revealed by functional characterization in tsA-201 cells. We found transcripts of these exons in mouse chromaffin cells, the cochlea, and the brain. Our data further suggest that Cav1.3-containing exons 11 and 32 constitute a significant part of native channels in the brain. We therefore investigated the effect of these splice variants on human disease variants. Splicing did not prevent the gating defects of the previously reported human pathogenic variant S652L, which further shifted the voltage-dependence of activation of exon 11-containing channels by more than -12 mV. In contrast, we found no evidence for gating changes of the <i>CACNA1D</i> missense variant R498L, located in exon 11, which has recently been identified in a patient with an epileptic syndrome. Our data demonstrate that alternative splicing outside the C-terminus involving exons 11 and 32 contributes to channel fine-tuning by stabilizing negative activation and inactivation gating properties of wild-type and mutant Cav1.3 channels.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9107257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Database mining analysis revealed the role of the putative H⁺/sugar transporter solute carrier family 45 in skin cutaneous melanoma.","authors":"Jiaheng Xie, Shujie Ruan, Zhechen Zhu, Ming Wang, Yuan Cao, Mengmeng Ou, Pan Yu, Jingping Shi","doi":"10.1080/19336950.2021.1956226","DOIUrl":"10.1080/19336950.2021.1956226","url":null,"abstract":"<p><p>Metabolic reprogramming is common in various cancers. Targeting metabolism to treat tumors is a hot research topic at present. Among them, changes in glucose metabolism in cancer have been widely studied. The Warburg effect maintains a high metabolic level in the tumor, accompanied by changes in glucose transporters. The transmembrane transport of sugar was previously thought to be mediated by SGLT and GLUT. Recently, the Solute Carrier Family(SLC) 45 family may be the third sugar transporter. But the role and value of the SLC45 family in melanoma, a highly malignant skin tumor, is unclear. Our study found that the four members of the SLC45 family, SLC45A1-SLC45A4, were differentially expressed in melanoma, but only SLC45A2 and SLC45A3 had prognostic guiding values. Further analysis revealed that the co-expression patterns of SLC45A2 and SLC45A3 were enriched in multiple metabolic pathways, suggesting their potential role in melanoma. In addition, SLC45A2 and SLC45A3 are also associated with immune cell infiltration. In conclusion, SLC45A2 and SLC45A3 are good prognostic indicators for melanoma and have guiding value for the treatment of melanoma in the future.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/cd/f3/KCHL_15_1956226.PMC8331014.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39264401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T-type channels in neuropathic pain - Villain or victim?","authors":"Norbert Weiss","doi":"10.1080/19336950.2020.1740487","DOIUrl":"https://doi.org/10.1080/19336950.2020.1740487","url":null,"abstract":"Neuropathic pain syndromes affect between 30 and 50% of the world population and represent a significant burden for patients, society, and healthcare systems. Many hypotheses have been formulated about the mechanisms of neuropathic pain among which elevated expression of T-type calcium channels in peripheral nociceptive nerve fibers (so-called “nociceptors”) is seen as a hallmark in several experimental pain models [1]. Nociceptors have their cell bodies in the dorsal root ganglia (DRG) and express predominantly the Cav3.2 channel subtype whose primary function is to regulate neuronal firing and synaptic transmission at dorsal horn synapses [2]. Given these important functions in peripheral sensory neurons, aberrant expression of T-type channels in primary pain fibers comes as a pertinent cellular mechanism of neuropathic pain syndromes. How this up-regulation of T-type channels occurs at a mechanistic level has been the subject of a great deal of research in recent years and several studies pointed to a role of post-translationalmodification of the channel protein. Post-translational modification refers to changes a protein may undergo after translation (cleavage and/or covalent addition of chemical moieties) and serves as a secondary level of control to fine tune its functional expression. While post-translational modification of proteins is an essential part of cellular homeostasis, it has become increasingly evident that this process is altered in pathological conditions including pain syndromes. Using a mouse model or peripheral nerve injury-induced neuropathic pain, Garcia-Caballero et al., reported a decreased ubiquitinylation of Cav3.2 channels in primary afferent nerve fibers [3]. Biochemical analysis revealed that this effect was mediated by the up-regulation of the deubiquitinylating enzyme USP5 resulting in the accumulation of Cav3.2 in the plasma membrane. Importantly, the authors showed that prophylactic knockdown of USP5, or prophylactic disruption of the Cav3.2/USP5 complex, was sufficient to prevent nerve-injury-induced mechanical and thermal hyperalgesia demonstrating the causal implication of the ubiquitinylation machinery in the development of neuropathic pain in this experimental model. In yet another study using the same experimental pain model, the authors reported a decreased SUMOylation of USP5 in peripheral nociceptive nerve fibers [4]. Given that SUMOylation of USP5 negatively regulates its ability to interact with Cav3.2, decreased SUMOylated USP5 during nerve injury would favor Cav3.2/USP5 interaction. This would add to the already elevated level of USP5, which would enhance the deubiquitinylation of Cav3.2 and further potentiate the expression of the channel in the plasma membrane. Asparagine (N)-linked glycosylation is another type of post-translational modification that has been reported to potentially contribute to peripheral painful diabetic neuropathy. Several in vitro studies have documented the functional impo","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19336950.2020.1740487","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37733892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutations in calmodulin-binding domains of TRPV4/6 channels confer invasive properties to colon adenocarcinoma cells.","authors":"Atousa Arbabian,&nbsp;Mircea Iftinca,&nbsp;Christophe Altier,&nbsp;Param Priya Singh,&nbsp;Hervé Isambert,&nbsp;Sylvie Coscoy","doi":"10.1080/19336950.2020.1740506","DOIUrl":"https://doi.org/10.1080/19336950.2020.1740506","url":null,"abstract":"<p><p>Transient receptor potential (TRP) channels form a family of polymodal cation channels gated by thermal, mechanical, or chemical stimuli, with many of them involved in the control of proliferation, apoptosis, or cell cycle. From an evolutionary point of view, TRP family is characterized by high conservation of duplicated genes originating from whole-genome duplication at the onset of vertebrates. The conservation of such \"ohnolog\" genes is theoretically linked to an increased probability of generating phenotypes deleterious for the organism upon gene mutation. We aimed to test experimentally the hypothesis that TRP mutations, in particular gain-of-function, could be involved in the generation of deleterious phenotypes involved in cancer, such as gain of invasiveness. Indeed, a number of TRP channels have been linked to cancer progression, and exhibit changes in expression levels in various types of cancers. However, TRP mutations in cancer have been poorly documented. We focused on 2 TRPV family members, TRPV4 and TRPV6, and studied the effect of putative gain-of-function mutations on invasiveness properties. TRPV channels have a C-terminal calmodulin-binding domain (CaMBD) that has important functions for regulating protein function, through different mechanisms depending on the channel (channel inactivation/potentiation, cytoskeleton regulation). We studied the effect of mutations mimicking constitutive phosphorylation in TRPV4 and TRPV6 CaMBDs: TRPV4 S823D, S824D and T813D, TRPV6 S691D, S692D and T702. We found that most of these mutants induced a strong gain of invasiveness of colon adenocarcinoma SW480 cells, both for TRPV4 and TRPV6. While increased invasion with TRPV6 S692D and T702D mutants was correlated to increased mutant channel activity, it was not the case for TRPV4 mutants, suggesting different mechanisms with the same global effect of gain in deleterious phenotype. This highlights the potential importance to search for TRP mutations involved in cancer.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19336950.2020.1740506","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37749566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The mutation L69P in the PAS domain of the hERG potassium channel results in LQTS by trafficking deficiency.","authors":"Tina Jenewein,&nbsp;Scott A Kanner,&nbsp;Daniel Bauer,&nbsp;Brigitte Hertel,&nbsp;Henry M Colecraft,&nbsp;Anna Moroni,&nbsp;Gerhard Thiel,&nbsp;Silke Kauferstein","doi":"10.1080/19336950.2020.1751522","DOIUrl":"https://doi.org/10.1080/19336950.2020.1751522","url":null,"abstract":"<p><p>The congenital long QT syndrome (LQTS) is a cardiac disorder characterized by a prolonged QT interval on the electrocardiogram and an increased susceptibility to ventricular arrhythmias and sudden cardiac death. A frequent cause for LQTS is mutations in the <i>KCNH2</i> gene (also known as the <i>human ether-a-go-go-related gene</i> or <i>hERG</i>), which reduce or modulate the potassium current I_Kr and hence alter cardiac repolarization. In a patient with a clinically diagnosed LQTS, we identified the mutation L69P in the N-terminal PAS (Per-Arnt-Sim) domain of hERG. Functional expression in HEK293 cells shows that a homotetrameric hERG channel reconstituted with only mutant subunits exhibits a drastically reduced surface expression of the channel protein thus leading to a diminished hERG current. Unlike many other mutations in the hERG-PAS domain the negative impact of the L69P substitution cannot be rescued by facilitated protein folding at a lower incubation temperature. Further, co-expression of wt and mutant monomers does not restore either wt like surface expression or the full hERG current. These results indicate L69P is a dominant negative mutation, with deficits which most likely occurs at the level of protein folding and subsequently inhibits trafficking to the plasma membrane. The functional deficits of the mutant channel support the clinical diagnosis of a LQTS.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19336950.2020.1751522","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37807269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}