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Channel protein trafficking and chaperones

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
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...
October 6, 2016: Current Pharmaceutical Design
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
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 2016: Journal of the American Heart Association
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
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
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
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
Matthew J Mulcahy, Sydney B Blattman, Francisco J Barrantes, Ronald J Lukas, Edward Hawrot
The α7-nicotinic acetylcholine receptor (α7-nAChR) is a ligand-gated ion channel widely expressed in vertebrates and is associated with numerous physiological functions. As transmembrane ion channels, α7-nAChRs need to be expressed on the surface of the plasma membrane to function. The receptor has been reported to associate with proteins involved with receptor biogenesis, modulation of receptor properties, as well as intracellular signaling cascades and some of these associated proteins may affect surface expression of α7-nAChRs...
2015: PloS One
Dong-Yun Han, Bo-Jhih Guan, Ya-Juan Wang, Maria Hatzoglou, Ting-Wei Mu
Gamma-aminobutyric acid type A (GABAA) receptors are the primary inhibitory ion channels in the mammalian central nervous system and play an essential role in regulating inhibition-excitation balance in neural circuits. The α1 subunit harboring the D219N mutation of GABAA receptors was reported to be retained in the endoplasmic reticulum (ER) and traffic inefficiently to the plasma membrane, leading to a loss of function of α1(D219N) subunits and thus idiopathic generalized epilepsy (IGE). We present the use of small molecule proteostasis regulators to enhance the forward trafficking of α1(D219N) subunits to restore their function...
September 18, 2015: ACS Chemical Biology
Daniel Wojciechowski, Martin Fischer, Christoph Fahlke
CLC-K chloride channels are expressed in the kidney and in the inner ear and require the accessory subunit barttin for proper function and membrane insertion. Barttin exerts multiple functions on CLC-proteins: it modifies protein stability and intracellular trafficking as well as channel activity, ion conduction, and gating. So far, the molecular determinants of these distinct barttin functions have remained elusive. Here we performed serial perturbation mutagenesis to identify the sequence determinants of barttin function...
July 24, 2015: Journal of Biological Chemistry
Luke H Chamberlain, Michael J Shipston
Protein S-acylation, the only fully reversible posttranslational lipid modification of proteins, is emerging as a ubiquitous mechanism to control the properties and function of a diverse array of proteins and consequently physiological processes. S-acylation results from the enzymatic addition of long-chain lipids, most typically palmitate, onto intracellular cysteine residues of soluble and transmembrane proteins via a labile thioester linkage. Addition of lipid results in increases in protein hydrophobicity that can impact on protein structure, assembly, maturation, trafficking, and function...
April 2015: Physiological Reviews
Agata M Trzcińska-Daneluti, Anthony Chen, Leo Nguyen, Ryan Murchie, Chong Jiang, Jason Moffat, Lawrence Pelletier, Daniela Rotin
Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding the Cystic fibrosis transmembrane conductance regulator (CFTR). ΔF508-CFTR, the most common disease-causing CF mutant, exhibits folding and trafficking defects and is retained in the endoplasmic reticulum, where it is targeted for proteasomal degradation. To identify signaling pathways involved in ΔF508-CFTR rescue, we screened a library of endoribonuclease-prepared short interfering RNAs (esiRNAs) that target ∼750 different kinases and associated signaling proteins...
June 2015: Molecular & Cellular Proteomics: MCP
Karsten Ruscher, Tadeusz Wieloch
The sigma-1 receptor (Sig-1R) is a single 25 kD polypeptide and a chaperone protein immersed in lipid rafts of the endoplasmic reticulum (ER) where it interacts with mitochondria at the mitochondria-associated ER membrane domain (MAM). Upon activation, the Sig-1R binds to the inositol trisphosphate receptor (IP3R), and modulates cellular calcium (Ca(2+)) homeostasis. Also, the activated Sig-1R modulates plasma membrane receptor and ion channel functions, and may regulate cellular excitability. Further, the Sig-1R promotes trafficking of lipids and proteins essential for neurotransmission, cell growth and motility...
January 2015: Journal of Pharmacological Sciences
Alexander Polster, Stefano Perni, Hicham Bichraoui, Kurt G Beam
Excitation-contraction (EC) coupling in skeletal muscle depends upon trafficking of CaV1.1, the principal subunit of the dihydropyridine receptor (DHPR) (L-type Ca(2+) channel), to plasma membrane regions at which the DHPRs interact with type 1 ryanodine receptors (RyR1) in the sarcoplasmic reticulum. A distinctive feature of this trafficking is that CaV1.1 expresses poorly or not at all in mammalian cells that are not of muscle origin (e.g., tsA201 cells), in which all of the other nine CaV isoforms have been successfully expressed...
January 13, 2015: Proceedings of the National Academy of Sciences of the United States of America
Yue Fu, Feng-Ming James Chang, David P Giedroc
CONSPECTUS: The human innate immune system has evolved the means to reduce the bioavailability of first-row late d-block transition metal ions to invading microbial pathogens in a process termed "nutritional immunity". Transition metals from Mn(II) to Zn(II) function as metalloenzyme cofactors in all living cells, and the successful pathogen is capable of mounting an adaptive response to mitigate the effects of host control of transition metal bioavailability. Emerging evidence suggests that Mn, Fe, and Zn are withheld from the pathogen in classically defined nutritional immunity, while Cu is used to kill invading microorganisms...
December 16, 2014: Accounts of Chemical Research
Dilshan Balasuriya, Lauren D'Sa, Ronel Talker, Elodie Dupuis, Fabrice Maurin, Patrick Martin, Franck Borgese, Olivier Soriani, J Michael Edwardson
The sigma-1 receptor is an endoplasmic reticulum chaperone protein, widely expressed in central and peripheral tissues, which can translocate to the plasma membrane and modulate the function of various ion channels. The human ether-à-go-go-related gene encodes hERG, a cardiac voltage-gated K(+) channel that is abnormally expressed in many human cancers and is known to interact functionally with the sigma-1 receptor. Our aim was to investigate the nature of the interaction between the sigma-1 receptor and hERG...
November 14, 2014: Journal of Biological Chemistry
Yue Jiang, Sandeepa Dey, Hiroaki Matsunami
In order to perform their designated functions, proteins require precise subcellular localizations. For cell-surface proteins, such as receptors and channels, they are able to transduce signals only when properly targeted to the cell membrane. Calreticulin is a multi-functional chaperone protein involved in protein folding, maturation, and trafficking. However, evidence has been accumulating that calreticulin can also negatively regulate the surface expression of certain receptors and channels. In these instances, depletion of calreticulin enhances cell-surface expression and function...
2014: Membranes
Kaiping Zhang, Duo Zhi, Ting Huang, Yan Gong, Meng Yan, Chen Liu, Ting Wei, Zengxiang Dong, Baoxin Li, Baofeng Yang
AIMS: The human ether-a-go-go-related gene (hERG) encodes the α subunit of the IKr, which plays an essential role in repolarization of action potentials. hERG channels are targeted by various pro-arrhythmic drugs. Berberine (BBR) was previously found to acutely inhibit hERG currents and prolong action potential duration. The present study aimed to determine long-term effects of BBR on the expression of 135kDa/155kDa hERG and the mechanism. METHODS AND RESULTS: hERG expression was assessed by western blot...
2014: Cellular Physiology and Biochemistry
Mohan Pabba, Adrian Y C Wong, Nina Ahlskog, Elitza Hristova, Dante Biscaro, Wissam Nassrallah, Johnny K Ngsee, Melissa Snyder, Jean-Claude Beique, Richard Bergeron
Sigma-1 receptors (σ-1Rs) are endoplasmic reticulum resident chaperone proteins implicated in many physiological and pathological processes in the CNS. A striking feature of σ-1Rs is their ability to interact and modulate a large number of voltage- and ligand-gated ion channels at the plasma membrane. We have reported previously that agonists for σ-1Rs potentiate NMDA receptor (NMDAR) currents, although the mechanism by which this occurs is still unclear. In this study, we show that in vivo administration of the selective σ-1R agonists (+)-SKF 10,047 [2S-(2α,6α,11R*]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol hydrochloride (N-allylnormetazocine) hydrochloride], PRE-084 (2-morpholin-4-ylethyl 1-phenylcyclohexane-1-carboxylate hydrochloride), and (+)-pentazocine increases the expression of GluN2A and GluN2B subunits, as well as postsynaptic density protein 95 in the rat hippocampus...
August 20, 2014: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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