Search results for "Ion transporter"
showing 10 items of 73 documents
Molecular determinants of the Arabidopsis AKT1 K+ channel ionic selectivity investigated by expression in yeast of randomly mutated channels
1999
International audience; The Avabidopsis thaliana K+ channel AKT1 was expressed in a yeast strain defective for K+ uptake at low K+ concentrations (<3 mM). Besides restoring K+ transport in this strain, AKT1 expression increased its tolerance to salt (NaCl or LiCl), whatever the external K+ concentration used (50 mu M, 5 mM, or 50 mM), We took advantage of the latter phenomenon for screening a library of channels randomly mutated in the region that shares homologies with the pore forming domain (the so-called P domain) of animal K+ channels (Shaker family). Cassette mutagenesis was performed using a degenerate oligonucleotide that was designed to ensure, theoretically, a single mutation per …
Mechanisms of action of metformin in type 2 diabetes: Effects on mitochondria and leukocyte-endothelium interactions.
2020
Type 2 diabetes (T2D) is a very prevalent, multisystemic, chronic metabolic disorder closely related to atherosclerosis and cardiovascular diseases. It is characterised by mitochondrial dysfunction and the presence of oxidative stress. Metformin is one of the safest and most effective anti-hyperglycaemic agents currently employed as first-line oral therapy for T2D. It has demonstrated additional beneficial effects, unrelated to its hypoglycaemic action, on weight loss and several diseases, such as cancer, cardiovascular disorders and metabolic diseases, including thyroid diseases. Despite the vast clinical experience gained over several decades of use, the mechanism of action of metformin i…
Bioelectrical Signals and Ion Channels in the Modeling of Multicellular Patterns and Cancer Biophysics
2016
AbstractBioelectrical signals and ion channels are central to spatial patterns in cell ensembles, a problem of fundamental interest in positional information and cancer processes. We propose a model for electrically connected cells based on simple biological concepts: i) the membrane potential of a single cell characterizes its electrical state; ii) the long-range electrical coupling of the multicellular ensemble is realized by a network of gap junction channels between neighboring cells; and iii) the spatial distribution of an external biochemical agent can modify the conductances of the ion channels in a cell membrane and the multicellular electrical state. We focus on electrical effects …
Loss of organic cation transporter 3 (Oct3) leads to enhanced proliferation and hepatocarcinogenesis
2017
// Johanna Vollmar 1 , Anja Lautem 2 , Ellen Closs 3 , Detlef Schuppan 4 , Yong Ook Kim 4 , Daniel Grimm 1 , Jens U. Marquardt 1 , Peter Fuchs 1 , Beate K. Straub 5 , Arno Schad 5 , Dirk Grundemann 6 , Jorn M. Schattenberg 1 , Nadine Gehrke 1 , Marcus A. Worns 1 , Jan Baumgart 7 , Peter R. Galle 1 and Tim Zimmermann 1 1 Department of Internal Medicine, Gastroenterology and Hepatology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany 2 Department of Hepatobiliary and Transplantation Surgery, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany 3 Department of Pharmacology, University Medical Center, Johannes Gutenberg-University Mainz, …
Functional inhibition of Oct leads to HNF4α upregulation
2021
Organic cation transporters (human, OCT; mouse, Oct) are responsible for the intracellular uptake and detoxification of a broad spectrum of endogenous and exogenous substrates. The OCT1 gene SLC22A1 (human; mouse, Scl22a1) is transactivated by hepatocyte nuclear factor 4α (human, HNF4α; mouse, Hnf4α). HNF4α is a master regulator of hepatocyte differentiation and is frequently associated with hepatocellular carcinoma (HCC). In addition, the downregulation of HNF4α is associated with enhanced fibrogenesis. Our recent study revealed that hepatocarcinogenesis and fibrosis were enhanced with the loss of Oct3 (gene, Slc22a3). Notably, differences in Hnf4α expression, and in cholestasis and fibros…
Loop diuretics decrease the renal elimination rate and increase the plasma levels of trimethylamine‐N‐oxide
2018
Aims Trimethylamine-N-oxide (TMAO) is a novel cardiovascular risk marker. We explored the association of commonly used cardiovascular medications with TMAO levels in patients and validated the identified associations in mice. Methods Detailed history of drug treatment was recorded in 300 patients with cardiovascular disease without diabetes in an observational, cross-sectional study. Animal study was performed in CD1 mice. Results Median plasma TMAO (interquartile range) level was 2.144 (1.570-3.104) μmol l-1 . Among nine cardiovascular drug groups, the use of loop diuretics (0.510 ± 0.296 in users vs. 0.336 ± 0.272 in nonusers, P = 0.008) and mineralocorticoid receptor antagonists (0.482 ±…
Usefulness of current candidate genetic markers to identify childhood cancer patients at risk for platinum-induced ototoxicity: Results of the Europe…
2020
Background Irreversible sensorineural hearing loss is a common side effect of platinum treatment with the potential to significantly impair the neurocognitive, social and educational development of childhood cancer survivors. Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in the FDA drug label and a pharmacogenetic guideline. The aim of this cross-sectional cohort study was to confirm the genetic associations in a large pan-European population and to evaluate the diagnostic accuracy of the genetic…
Tetraspanin CD63 controls basolateral sorting of organic cation transporter 2 in renal proximal tubules.
2016
CD63 is a ubiquitously expressed member of the tetraspanin superfamily. Using a mating-based split-ubiquitin-yeast 2-hybrid system, pull-down experiments, total internal reflection fluorescence microscopy, Forster resonance energy transfer, and biotinylation assays, we found that CD63 interacts with human organic cation transporter 2 (hOCT2), which transports endogenous and exogenous substrates, such as neurotransmitters and drugs in several epithelial cells. CD63 overexpression affects cellular localization of hOCT2 expressed in human embryonic kidney (HEK)293 cells. Studies with CD63-knockout mice indicate that in renal proximal tubules, CD63 determines the insertion of the mouse ortholog…
A Thermodynamic Model of Monovalent Cation Homeostasis in the Yeast Saccharomyces cerevisiae
2016
Cationic and heavy metal toxicity is involved in a substantial number of diseases in mammals and crop plants. Therefore, the understanding of tightly regulated transporter activities, as well as conceiving the interplay of regulatory mechanisms, is of substantial interest. A generalized thermodynamic description is developed for the complex interplay of the plasma membrane ion transporters, membrane potential and the consumption of energy for maintaining and restoring specific intracellular cation concentrations. This concept is applied to the homeostasis of cation concentrations in the yeast cells of S. cerevisiae. The thermodynamic approach allows to model passive ion fluxes driven by the…
Permeating disciplines: Overcoming barriers between molecular simulations and classical structure-function approaches in biological ion transport
2017
Ion translocation across biological barriers is a fundamental requirement for life. In many cases, controlling this process-for example with neuroactive drugs-demands an understanding of rapid and reversible structural changes in membrane-embedded proteins, including ion channels and transporters. Classical approaches to electrophysiology and structural biology have provided valuable insights into several such proteins over macroscopic, often discontinuous scales of space and time. Integrating these observations into meaningful mechanistic models now relies increasingly on computational methods, particularly molecular dynamics simulations, while surfacing important challenges in data manage…