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Channel protein trafficking and chaperones

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https://www.readbyqxmd.com/read/29694233/functional-features-of-the-finger-domain-of-deg-enac-channels-mec-4-and-unc-8
#1
Cristina Matthewman, Christina K Johnson, David M Miller Iii, Laura Bianchi
UNC-8 and MEC-4 are two members of the DEG/ENaC family of voltage-independent Na+ channels that share a high degree of sequence homology and functional similarity. For example, both can be hyperactivated by genetic mutations (UNC-8(d) and MEC-4(d)) that induce neuronal death by necrosis. Both depend in vivo on chaperone protein MEC-6 for function, as demonstrated by the finding that neuronal death induced by hyperactive UNC-8 and MEC-4 channels is prevented by null mutations in mec-6. UNC-8 and MEC-4 differ functionally in three major ways: 1) MEC-4 is calcium permeable whereas UNC-8 is not; 2) UNC-8, but not MEC-4, is blocked by extracellular calcium and magnesium in the micromolar range; 3) MEC-6 increases the number of MEC-4 channels at the cell surface in oocytes but does not have this effect on UNC-8...
April 25, 2018: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/29555765/ligand-channel-in-pharmacologically-stabilized-rhodopsin
#2
Daniel Mattle, Bernd Kuhn, Johannes Aebi, Marc Bedoucha, Demet Kekilli, Nathalie Grozinger, Andre Alker, Markus G Rudolph, Georg Schmid, Gebhard F X Schertler, Michael Hennig, Jörg Standfuss, Roger J P Dawson
In the degenerative eye disease retinitis pigmentosa (RP), protein misfolding leads to fatal consequences for cell metabolism and rod and cone cell survival. To stop disease progression, a therapeutic approach focuses on stabilizing inherited protein mutants of the G protein-coupled receptor (GPCR) rhodopsin using pharmacological chaperones (PC) that improve receptor folding and trafficking. In this study, we discovered stabilizing nonretinal small molecules by virtual and thermofluor screening and determined the crystal structure of pharmacologically stabilized opsin at 2...
April 3, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29402832/the-cftr-associated-ligand-arrests-the-trafficking-of-the-mutant-%C3%AE-f508-cftr-channel-in-the-er-contributing-to-cystic-fibrosis
#3
Emily Bergbower, Clement Boinot, Inna Sabirzhanova, William Guggino, Liudmila Cebotaru
BACKGROUND/AIMS: The CFTR-Associated Ligand (CAL), a PDZ domain containing protein with two coiled-coil domains, reduces cell surface WT CFTR through degradation in the lysosome by a well-characterized mechanism. However, CAL's regulatory effect on ΔF508 CFTR has remained almost entirely uninvestigated. METHODS: In this study, we describe a previously unknown pathway for CAL by which it regulates the membrane expression of ΔF508 CFTR through arrest of ΔF508 CFTR trafficking in the endoplasmic reticulum (ER) using a combination of cell biology, biochemistry and electrophysiology...
2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29296759/a-specialized-pathway-for-erythroid-iron-delivery-through-lysosomal-trafficking-of-transferrin-receptor-2
#4
Shadi Khalil, Maja Holy, Stephen Grado, Robert Fleming, Ryo Kurita, Yukio Nakamura, Adam Goldfarb
Erythroid progenitors are the largest consumers of iron in the human body. In these cells, a high flux of iron must reach the mitochondrial matrix to form sufficient heme to support hemoglobinization. Canonical erythroid iron trafficking occurs via the first transferrin receptor (TfR1)-mediated endocytosis of diferric-transferrin into recycling endosomes, where ferric iron is released, reduced, and exported to the cytosol via DMT1. However, mice lacking TfR1 or DMT1 demonstrate residual erythropoiesis, suggesting additional pathways for iron use...
June 27, 2017: Blood Advances
https://www.readbyqxmd.com/read/29109154/hierarchical-protein-targeting-and-secretion-is-controlled-by-an-affinity-switch-in-the-type-iii-secretion-system-of-enteropathogenic-escherichia-coli
#5
Athina G Portaliou, Konstantinos C Tsolis, Maria S Loos, Vassileia Balabanidou, Josep Rayo, Alexandra Tsirigotaki, Valerie F Crepin, Gad Frankel, Charalampos G Kalodimos, Spyridoula Karamanou, Anastassios Economou
Type III secretion (T3S), a protein export pathway common to Gram-negative pathogens, comprises a trans-envelope syringe, the injectisome, with a cytoplasm-facing translocase channel. Exported substrates are chaperone-delivered to the translocase, EscV in enteropathogenic Escherichia coli, and cross it in strict hierarchical manner, for example, first "translocators", then "effectors". We dissected T3S substrate targeting and hierarchical switching by reconstituting them in vitro using inverted inner membrane vesicles...
December 1, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28763460/inhibitory-effects-and-mechanism-of-dihydroberberine-on-herg-channels-expressed-in-hek293-cells
#6
Dahai Yu, Lin Lv, Li Fang, Bo Zhang, Junnan Wang, Ge Zhan, Lei Zhao, Xin Zhao, Baoxin Li
The human ether-a-go-go-related gene (hERG) potassium channel conducts rapid delayed rectifier potassium currents (IKr) and contributes to phase III cardiac action potential repolarization. Drugs inhibit hERG channels by binding to aromatic residues in hERG helixes. Berberine (BBR) has multiple actions, and its hydrogenated derivative dihydroberberine (DHB) is a potential candidate for developing new drugs. Previous studies have demonstrated that BBR blocks hERG channels and prolongs action potential duration (APD)...
2017: PloS One
https://www.readbyqxmd.com/read/28607619/molecular-mechanisms-underlying-the-pilsicainide-induced-stabilization-of-herg-proteins-in-transfected-mammalian-cells
#7
Takeshi Onohara, Ichiro Hisatome, Yasutaka Kurata, Peili Li, Tomomi Notsu, Kumi Morikawa, Naoyuki Otani, Akio Yoshida, Kazuhiko Iitsuka, Masaru Kato, Junichiro Miake, Haruaki Ninomiya, Katsumi Higaki, Yasuaki Shirayoshi, Takashi Nishihara, Toshiyuki Itoh, Yoshinobu Nakamura, Motonobu Nishimura
BACKGROUND: Pilsicainide, classified as a relatively selective Na(+) channel blocker, also has an inhibitory action on the rapidly-activating delayed-rectifier K(+) current (IKr ) through human ether-a-go-go-related gene (hERG) channels. We studied the effects of chronic exposure to pilsicainide on the expression of wild-type (WT) hERG proteins and WT-hERG channel currents, as well as on the expression of mutant hERG proteins, in a heterologous expression system. METHODS: HEK293 cells stably expressing WT or mutant hERG proteins were subjected to Western blotting, immunofluorescence microscopy and patch-clamp experiments...
June 2017: Journal of Arrhythmia
https://www.readbyqxmd.com/read/28559331/the-potra-domains-of-toc75-exhibit-chaperone-like-function-to-facilitate-import-into-chloroplasts
#8
Patrick K O'Neil, Lynn G L Richardson, Yamuna D Paila, Grzegorz Piszczek, Srinivas Chakravarthy, Nicholas Noinaj, Danny Schnell
Protein trafficking across membranes is an essential function in cells; however, the exact mechanism for how this occurs is not well understood. In the endosymbionts, mitochondria and chloroplasts, the vast majority of proteins are synthesized in the cytoplasm as preproteins and then imported into the organelles via specialized machineries. In chloroplasts, protein import is accomplished by the TOC (translocon on the outer chloroplast membrane) and TIC (translocon on the inner chloroplast membrane) machineries in the outer and inner envelope membranes, respectively...
June 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28521025/mechanism-of-as2o3-induced-action-potential-prolongation-and-using-hips-cms-to-evaluate-the-rescue-efficacy-of-drugs-with-different-rescue-mechanism
#9
Meng Yan, Lifang Feng, Yanhui Shi, Junnan Wang, Yan Liu, Fengmei Li, Baoxin Li
Arsenic trioxide (As2O3) has been verified as a breakthrough in the management of acute promyelocytic leukemia in recent decades. However, cardiotoxicity, especially long QT syndrome (LQTS) has become the most important issue during As2O3 treatment. The characterized mechanisms behind this adverse effect are inhibition of cardiac hERG channel trafficking and increase of cardiac calcium currents. In our study, we found a new pathway underlying As2O3-induced cardiotoxicity that As2O3 accelerates lysosomal degradation of hERG on plasma membrane after using brefeldin A (BFA) to block protein trafficking...
August 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28342889/heteromeric-complexes-of-aldo-keto-reductase-auxiliary-k-v-%C3%AE-subunits-akr6a-regulate-sarcolemmal-localization-of-k-v-1-5-in-coronary-arterial-myocytes
#10
Matthew A Nystoriak, Deqing Zhang, Ganapathy Jagatheesan, Aruni Bhatnagar
Redox-sensitive potassium channels consisting of the voltage-gated K+ (KV ) channel pore subunit KV 1.5 regulate resting membrane potential and thereby contractility of vascular smooth muscle cells. Members of the KV 1 family associate with cytosolic auxiliary β subunits, which are members of the aldo-keto reductase (AKR) superfamily (AKR6A subfamily). The Kvβ subunits have been proposed to regulate Kv1 gating via pyridine nucleotide cofactor binding. However, the molecular identity of KV β subunits that associate with native KV 1...
October 1, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28294298/proteins-and-chemical-chaperones-involved-in-neuronal-nicotinic-receptor-expression-and-function-an-update
#11
REVIEW
Arianna Crespi, Sara Francesca Colombo, Cecilia Gotti
Neuronal nicotinic acetylcholine receptors (nAChRs) are a family of acetylcholine-(ACh) gated cation channels and their homeostasis or proteostasis is essential for the correct physiology of the central and peripheral nervous systems. The proteostasis network regulates the folding, assembly, degradation and trafficking of nAChRs in order to ensure their efficient functional cell surface expression. However, as nAChRs are multisubunit, multispan, integral membrane proteins, the folding and assembly is a very inefficient process, and only a small portion of subunits can form functional pentamers...
March 13, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28256585/lrp1-influences-trafficking-of-n-type-calcium-channels-via-interaction-with-the-auxiliary-%C3%AE-2%C3%AE-1-subunit
#12
Ivan Kadurin, Simon W Rothwell, Beatrice Lana, Manuela Nieto-Rostro, Annette C Dolphin
Voltage-gated Ca(2+) (CaV) channels consist of a pore-forming α1 subunit, which determines the main functional and pharmacological attributes of the channel. The CaV1 and CaV2 channels are associated with auxiliary β- and α2δ-subunits. The molecular mechanisms involved in α2δ subunit trafficking, and the effect of α2δ subunits on trafficking calcium channel complexes remain poorly understood. Here we show that α2δ-1 is a ligand for the Low Density Lipoprotein (LDL) Receptor-related Protein-1 (LRP1), a multifunctional receptor which mediates trafficking of cargoes...
March 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28001373/direct-measurement-of-trafficking-of-the-cystic-fibrosis-transmembrane-conductance-regulator-to-the-cell-surface-and-binding-to-a-chemical-chaperone
#13
Zhihui Zhang, Michael M Baksh, M G Finn, David K Heidary, Christopher I Richards
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) result in the disease cystic fibrosis. Deletion of Phe508, the most prevalent mutation associated with this disease, disrupts trafficking of the protein. Small molecule correctors yield moderate improvements in the trafficking of ΔF508-CFTR to the plasma membrane. It is currently not known if correctors increase the level of trafficking through improved cargo loading of transport vesicles or through direct binding to CFTR. Real-time measurements of trafficking were utilized to identify the mechanistic details of chemical, biochemical, and thermal factors that impact CFTR correction, using the corrector molecule VX-809, a secondary mutation (I539T), and low-temperature conditions...
January 10, 2017: Biochemistry
https://www.readbyqxmd.com/read/27719636/rnf5-dab2-and-friends-novel-drug-targets-for-cystic-fibrosis
#14
REVIEW
Elvira Sondo, Emanuela Pesce, Valeria Tomati, Monica Marini, Nicoletta Pedemonte
BACKGROUND: Deletion of phenylalanine 508 is the most frequent mutation causing cystic fibrosis. It causes multiple defects: 1) misfolding of the protein causing retention at the ER (processing defect); 2) reduced channel activity (gating defect); 3) reduced plasma membrane residency time due to increased internalization rate and defective recycling. METHODS: Druggability of F508del-CFTR was demonstrated by several studies. Correctors are molecules able to improve maturation and trafficking to the membrane of F508del- CFTR...
2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/27486162/peptidomimetic-targeting-of-cav%C3%AE-2-overcomes-dysregulation-of-the-l-type-calcium-channel-density-and-recovers-cardiac-function
#15
Francesca Rusconi, Paola Ceriotti, Michele Miragoli, Pierluigi Carullo, Nicolò Salvarani, Marcella Rocchetti, Elisa Di Pasquale, Stefano Rossi, Maddalena Tessari, Silvia Caprari, Magali Cazade, Paolo Kunderfranco, Jean Chemin, Marie-Louise Bang, Fabio Polticelli, Antonio Zaza, Giuseppe Faggian, Gianluigi Condorelli, Daniele Catalucci
BACKGROUND: L-type calcium channels (LTCCs) play important roles in regulating cardiomyocyte physiology, which is governed by appropriate LTCC trafficking to and density at the cell surface. Factors influencing the expression, half-life, subcellular trafficking, and gating of LTCCs are therefore critically involved in conditions of cardiac physiology and disease. METHODS: Yeast 2-hybrid screenings, biochemical and molecular evaluations, protein interaction assays, fluorescence microscopy, structural molecular modeling, and functional studies were used to investigate the molecular mechanisms through which the LTCC Cavβ2 chaperone regulates channel density at the plasma membrane...
August 16, 2016: Circulation
https://www.readbyqxmd.com/read/27207958/variants-of-transient-receptor-potential-melastatin-member-4-in-childhood-atrioventricular-block
#16
Ninda Syam, Stéphanie Chatel, Lijo Cherian Ozhathil, Valentin Sottas, Jean-Sébastien Rougier, Alban Baruteau, Estelle Baron, Mohamed-Yassine Amarouch, Xavier Daumy, Vincent Probst, Jean-Jacques Schott, Hugues Abriel
BACKGROUND: Transient receptor potential melastatin member 4 (TRPM4) is a nonselective cation channel. TRPM4 mutations have been linked to cardiac conduction disease and Brugada syndrome. The mechanisms underlying TRPM4-dependent conduction slowing are not fully understood. The aim of this study was to characterize TRPM4 genetic variants found in patients with congenital or childhood atrioventricular block. METHODS AND RESULTS: Ninety-one patients with congenital or childhood atrioventricular block were screened for candidate genes...
May 20, 2016: Journal of the American Heart Association
https://www.readbyqxmd.com/read/27199074/pharmacological-rescue-of-herg-currents-carried-out-by-g604s-and-wide-type-herg-co-expression
#17
Jianhua Huo, Aifeng Zhang, Xueyan Guo, Hua Qiang, Ping Liu, Ling Bai, Aiqun Ma
Mutations in human ether-a-go-go-related gene (hERG) can lead to type 2 long-QT syndrome (LQT2). The authors previously identified the hERG mutation G604S results in a loss of function and obviously decreased current amplitude and impaired channel protein trafficking when co-expressed with WT-hERG. The present study further investigates the biological and electrophysiological consequences of pharmacologic chaperones in HEK293 cells expressing G604S-hERG or co-expressing G604S-hERG and WT-hERG. It was found that a low temperature (27°C), thapsigargin, NS1643 and E-4031 fail to rescue the G604S mutation...
September 2016: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/26953247/pharmacoperones-as-a-new-therapeutic-approach-in-vitro-identification-and-in-vivo-validation-of-bioactive-molecules
#18
REVIEW
Alfredo Ulloa-Aguirre, P Michael Conn
In many conformational diseases caused by protein mutations, the intracellular traffic of the misfolded protein is compromised, leading to reduced or abolished function of the affected protein. Pharmacoperones (from "pharmacological chaperones") are compounds that enter cells and serve as a molecular scaffold to aid misfolded mutant proteins to fold properly and adopt a stable, low-energy native conformation compatible with proper intracellular trafficking. The use of pharmacoperones represents the most promising therapeutic approach to treat misfolding disorders...
2016: Current Drug Targets
https://www.readbyqxmd.com/read/26303164/high-glucose-represses-herg-k-channel-expression-through-trafficking-inhibition
#19
Yuan-Qi Shi, Meng Yan, Li-Rong Liu, Xiao Zhang, Xue Wang, Huai-Ze Geng, Xin Zhao, Bao-Xin Li
BACKGROUND/AIMS: Abnormal QT prolongation is the most prominent cardiac electrical disturbance in patients with diabetes mellitus (DM). It is well known that the human ether-ago-go-related gene (hERG) controls the rapid delayed rectifier K+ current (IKr) in cardiac cells. The expression of the hERG channel is severely down-regulated in diabetic hearts, and this down-regulation is a critical contributor to the slowing of repolarization and QT prolongation. However, the intracellular mechanisms underlying the diabetes-induced hERG deficiency remain unknown...
2015: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/26271031/estradiol-regulates-human-qt-interval-acceleration-of-cardiac-repolarization-by-enhanced-kcnh2-membrane-trafficking
#20
Lars Anneken, Stefan Baumann, Patrick Vigneault, Peter Biliczki, Corinna Friedrich, Ling Xiao, Zenawit Girmatsion, Ina Takac, Ralf P Brandes, Stefan Kissler, Inka Wiegratz, Sven Zumhagen, Birgit Stallmeyer, Stefan H Hohnloser, Thomas Klingenheben, Eric Schulze-Bahr, Stanley Nattel, Joachim R Ehrlich
BACKGROUND: Modulation of cardiac repolarization by sexual hormones is controversial and hormonal effects on ion channels remain largely unknown. In the present translational study, we therefore assessed the relationship between QTc duration and gonadal hormones and studied underlying mechanisms. METHODS AND RESULTS: We measured hormone levels and QTc intervals in women during clomiphene stimulation for infertility and women before, during, and after pregnancy. Three heterozygous LQT-2 patients (KCNH2-p...
February 14, 2016: European Heart Journal
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