Cardiotonic Steroids: Potential Endogenous Sodium Pump Ligands with Diverse Function11

2002 ◽  
Vol 227 (8) ◽  
pp. 561-569 ◽  
Author(s):  
Renata I. Dmitrieva ◽  
Peter A. Doris
Keyword(s):  
Binding Site ◽  
Intracellular Signaling ◽  
Sodium Pump ◽  
Cellular Level ◽  
Extracellular Potassium ◽  
Sodium Potassium ◽  
A Cell ◽  
Body Fluid Balance ◽  
Sodium And Potassium ◽  
Insight Into

The highly conserved cardiotonic steroid (CS) binding site present on the ubiquitous membrane sodium pump, sodium, potassium-ATPase, appears to have been conserved by no force other than its capacity to bind CS: a family that includes plant-derived cardiac glycosides and putative endogenous vertebrate counterparts. Binding of ligand is inhibited by increased extracellular potassium. This implies functional coordination because inhibition of the sodium pump would be counterproductive when extracellular potassium is elevated. The interesting biology of the CS binding site continues to stimulate investigations into the identity of endogenous ligands, their role as pump regulators at the cellular level, and as mediators of body fluid balance and blood pressure regulation. In addition to inhibition of sodium and potassium transport, there is considerable recent evidence suggesting that the sodium pump may act as a cell signaling receptor activated by CS binding and responding by coordination of intracellular signaling pathways that can be dependent on and also independent of the reduction in transmembrane ion flux resulting directly from pump inhibition. This signaling may influence cell survival, growth, and differentiation. Recent insight into the biology of pump regulation by CS is reviewed.

Effects of Synthetic Atrial Natriuretic Peptides on Sodium-Potassium Transport in Human Erythrocytes

1985 ◽  
Vol 69 (2) ◽  
pp. 223-226 ◽  
Author(s):  
G. A. Sagnella ◽  
D. A. Nolan ◽  
A. C. Shore ◽  
G. A. MacGregor
Keyword(s):  
Loop Diuretic ◽  
Sodium Pump ◽  
Human Erythrocytes ◽  
Atrial Natriuretic Peptides ◽  
Sodium Potassium ◽  
Potassium Ion Transport ◽  
Wide Range ◽  
Natriuretic Effect ◽  
Cotransport System ◽  
Sodium And Potassium

1. The effects of synthetic human and rat atrial peptides on sodium and potassium ion transport has been investigated in intact human erythrocytes. 2. The effects of these peptides have been tested on the active, sodium pump-dependent (ouabain-sensitive) and on the sodium-potassium cotransport system (bumetanide-sensitive) with 86Rb used as a tracer. 3. Human (α-ANP, 28 amino acids) or rat (atriopeptin III) atrial peptides, over a wide range of concentrations, did not influence the uptake of 86Rb in either the ouabain-sensitive or the bumetanide-sensitive transport system. 4. These results suggest that the natriuretic effect of the atrial peptides is not mediated through inhibition of the sodium pump or the loop-diuretic-sensitive Na-K cotransport.

scholarly journals Gastric proton pump with two occluded K+ engineered with sodium pump-mimetic mutations

2021 ◽  
Author(s):  
Kazuhiro Abe ◽  
Kenta Yamamoto ◽  
Katsumasa Irie ◽  
Tomohiro Nishizawa ◽  
Atsunori Oshima
Keyword(s):  
Binding Site ◽  
Sodium Pump ◽  
Cation Binding ◽  
Marked Contrast ◽  
Cation Binding Site ◽  
Anomalous Density ◽  
Quadruple Mutant ◽  
Gastric Proton Pump ◽  
The One ◽  
Insight Into

Abstract The gastric H+,K+-ATPase mediates electroneutral exchange of 1H+/1K+ per ATP hydrolysed across the membrane. Previous structural analysis of the K+-occluded E2-Pi form of H+,K+-ATPase showed a single bound K+ at cation-binding site II, in marked contrast to the two K+ occluded at sites I and II of the closely-related Na+,K+-ATPase which mediates electrogenic 3Na+/2K+ translocation across the membrane. The two pumps show significant differences in structure in and around Site I, but which are critical for blocking K+ binding in the gastric pump and contribute to binding in the sodium pump is unclear. We have a series of crystal structures and a cryo-EM structure of H+,K+-ATPase mutants with changes in the vicinity of site I based on the structure of the sodium pump. The number of bound Rb+, determined by its anomalous dispersion, remains one in the luminal-open E2BeF form of the Lys791Ser single mutant and Lys791Ser/Glu820Asp double mutant, mutation that could create space and may directly bind the cation. We next introduced mutations in peripheral residues Try340Asn and Glu936Val. A strong and spread-out Rb+ anomalous density observed in the quadruple mutant suggests that a certain population ATPases has two Rb+ bound. We then added gate-closing mutation Try799Trp and determined its cryo-EM structure in the occluded E2-AlF form. This quintuple mutant unambiguously has two separate densities at the cation-binding site. The step-wise construction of the K+ binding site offers new insight into how it is blocked in the one pump and constituted in the other.

Nanoparticle-plasma Membrane Interactions: Thermodynamics, Toxicity and Cellular Response

2020 ◽  
Vol 27 (20) ◽  
pp. 3330-3345
Author(s):  
Ana G. Rodríguez-Hernández ◽  
Rafael Vazquez-Duhalt ◽  
Alejandro Huerta-Saquero
Keyword(s):  
Gene Expression ◽  
Immune Responses ◽  
Cellular Response ◽  
Cellular Level ◽  
Membrane Interactions ◽  
Daily Lives ◽  
Cellular Physiology ◽  
Associated Proteins ◽  
First Contact ◽  
Insight Into

Nanomaterials have become part of our daily lives, particularly nanoparticles contained in food, water, cosmetics, additives and textiles. Nanoparticles interact with organisms at the cellular level. The cell membrane is the first protective barrier against the potential toxic effect of nanoparticles. This first contact, including the interaction between the cell membranes -and associated proteins- and the nanoparticles is critically reviewed here. Nanoparticles, depending on their toxicity, can cause cellular physiology alterations, such as a disruption in cell signaling or changes in gene expression and they can trigger immune responses and even apoptosis. Additionally, the fundamental thermodynamics behind the nanoparticle-membrane and nanoparticle-proteins-membrane interactions are discussed. The analysis is intended to increase our insight into the mechanisms involved in these interactions. Finally, consequences are reviewed and discussed.

scholarly journals Maturation of the Na,K-ATPase in the Endoplasmic Reticulum in Health and Disease

2021 ◽  
Author(s):  
Vitalii Kryvenko ◽  
Olga Vagin ◽  
Laura A. Dada ◽  
Jacob I. Sznajder ◽  
István Vadász
Keyword(s):  
Endoplasmic Reticulum ◽  
Intracellular Signaling ◽  
Loss Of Function ◽  
Α Subunit ◽  
Rate Limiting Step ◽  
Atpase Subunits ◽  
A Cell ◽  
Health And Disease ◽  
And Function ◽  
Rate Limiting

Abstract The Na,K-ATPase establishes the electrochemical gradient of cells by driving an active exchange of Na+ and K+ ions while consuming ATP. The minimal functional transporter consists of a catalytic α-subunit and a β-subunit with chaperon activity. The Na,K-ATPase also functions as a cell adhesion molecule and participates in various intracellular signaling pathways. The maturation and trafficking of the Na,K-ATPase include co- and post-translational processing of the enzyme in the endoplasmic reticulum (ER) and the Golgi apparatus and subsequent delivery to the plasma membrane (PM). The ER folding of the enzyme is considered as the rate-limiting step in the membrane delivery of the protein. It has been demonstrated that only assembled Na,K-ATPase α:β-complexes may exit the organelle, whereas unassembled, misfolded or unfolded subunits are retained in the ER and are subsequently degraded. Loss of function of the Na,K-ATPase has been associated with lung, heart, kidney and neurological disorders. Recently, it has been shown that ER dysfunction, in particular, alterations in the homeostasis of the organelle, as well as impaired ER-resident chaperone activity may impede folding of Na,K-ATPase subunits, thus decreasing the abundance and function of the enzyme at the PM. Here, we summarize our current understanding on maturation and subsequent processing of the Na,K-ATPase in the ER under physiological and pathophysiological conditions. Graphic Abstract

scholarly journals Structural Insight into the Two-Step Mechanism of PAI-1 Inhibition by Small Molecule TM5484

2021 ◽  
Vol 22 (3) ◽  
pp. 1482 ◽  
Author(s):  
Machteld Sillen ◽  
Toshio Miyata ◽  
Douglas E. Vaughan ◽  
Sergei V. Strelkov ◽  
Paul J. Declerck
Keyword(s):  
Binding Site ◽  
Small Molecule ◽  
Intracellular Signaling ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Joint Region ◽  
Flexible Joint ◽  
Step Mechanism ◽  
Pai 1

Plasminogen activator inhibitor-1 (PAI-1), a key regulator of the fibrinolytic system, is the main physiological inhibitor of plasminogen activators. By interacting with matrix components, including vitronectin (Vn), PAI-1 plays a regulatory role in tissue remodeling, cell migration, and intracellular signaling. Emerging evidence points to a role for PAI-1 in various pathological conditions, including cardiovascular diseases, cancer, and fibrosis. Targeting PAI-1 is therefore a promising therapeutic strategy in PAI-1-related pathologies. A class of small molecule inhibitors including TM5441 and TM5484, designed to bind the cleft in the central β-sheet A of PAI-1, showed to be potent PAI-1 inhibitors in vivo. However, their binding site has not yet been confirmed. Here, we report two X-ray crystallographic structures of PAI-1 in complex with TM5484. The structures revealed a binding site at the flexible joint region, which is distinct from the presumed binding site. Based on the structural analysis and biochemical data we propose a mechanism for the observed dose-dependent two-step mechanism of PAI-1 inhibition. By binding to the flexible joint region in PAI-1, TM5484 might restrict the structural flexibility of this region, thereby inducing a substrate form of PAI-1 followed by a conversion to an inert form.

scholarly journals Electrolyte imbalances in patients with severe coronavirus disease 2019 (COVID-19)

2020 ◽  
Vol 57 (3) ◽  
pp. 262-265 ◽  
Author(s):  
Giuseppe Lippi ◽  
Andrew M South ◽  
Brandon Michael Henry
Keyword(s):  
Weighted Mean Difference ◽  
Severe Disease ◽  
Total Sample ◽  
Pooled Analysis ◽  
Severe Form ◽  
Electrolyte Imbalance ◽  
Sodium Potassium ◽  
Impact Patient Care ◽  
Insight Into ◽  
Electrolyte Abnormalities

Background Early studies have reported various electrolyte abnormalities at admission in patients who progress to the severe form of coronavirus disease 2019 (COVID-19). As electrolyte imbalance may not only impact patient care, but provide insight into the pathophysiology of COVID-19, we aimed to analyse all early data reported on electrolytes in COVID-19 patients with and without severe form. Methods An electronic search of Medline (PubMed interface), Scopus and Web of Science was performed for articles comparing electrolytes (sodium, potassium, chloride and calcium) between COVID-19 patients with and without severe disease. A pooled analysis was performed to estimate the weighted mean difference (WMD) with 95% confidence interval. Results Five studies with a total sample size of 1415 COVID-19 patients. Sodium was significantly lower in patients with severe COVID-19 (WMD: –0.91 mmol/L [95% CI: –1.33 to –0.50 mmol/L]). Similarly, potassium was also significantly lower in COVID-19 patients with severe disease (WMD: –0.12 mmol/L [95% CI: –0.18 to –0.07 mmol/L], I2=33%). For chloride, no statistical differences were observed between patients with severe and non-severe COVID-19 (WMD: 0.30 mmol/L [95% CI: –0.41 to 1.01 mmol/L]). For calcium, a statistically significant lower concentration was noted in patients with severe COVID-19 (WMD: –0.20 mmol/L [95% CI: –0.25 to –0.20 mmol/L]). Conclusions This pooled analysis confirms that COVID-19 severity is associated with lower serum concentrations of sodium, potassium and calcium. We recommend electrolytes be measured at initial presentation and serially monitored during hospitalization in order to establish timely and appropriate corrective actions.

scholarly journals Changes in the Membrane Permeability of Frog's Sartorius Muscle Fibers in Ca-Free EDTA Solution

1963 ◽  
Vol 47 (2) ◽  
pp. 379-392 ◽  
Author(s):  
H. Kimizuka ◽  
K. Koketsu
Keyword(s):  
Membrane Permeability ◽  
Chloride Content ◽  
Chloride Ions ◽  
Sartorius Muscle ◽  
Constant Field ◽  
Sodium Influx ◽  
Sodium Potassium ◽  
Edta Solution ◽  
Frog Sartorius ◽  
Sodium And Potassium

The changes in the membrane permeability to sodium, potassium, and chloride ions as well as the changes in the intracellular concentration of these ions were studied on frog sartorius muscles in Ca-free EDTA solution. It was found that the rate constants for potassium and chloride efflux became almost constant within 10 minutes in the absence of external calcium ions, that for potassium increasing to 1.5 to 2 times normal and that for chloride decreasing about one-half. The sodium influx in Ca-free EDTA solution, between 30 and 40 minutes, was about 4 times that in Ringer's solution. The intracellular sodium and potassium contents did not change appreciably but the intracellular chloride content had increased to about 4 times normal after 40 minutes. By applying the constant field theory to these results, it was concluded that (a) PCl did not change appreciably whereas PK decreased to a level that, in the interval between 10 and 40 minutes, was about one-half normal, (b) PNa increased until between 30 and 40 minutes it was about 8 times normal. The low value of the membrane potential between 30 and 40 minutes was explained in terms of the changes in the membrane permeability and the intracellular ion concentrations. The mechanism for membrane depolarization in this solution was briefly discussed.

G-protein-coupled receptors signalling at the cell nucleus: an emerging paradigmThis paper is one of a selection of papers published in this Special Issue, entitled The Nucleus: A Cell Within A Cell.

2006 ◽  
Vol 84 (3-4) ◽  
pp. 287-297 ◽  
Author(s):  
Fernand Gobeil ◽  
Audrey Fortier ◽  
Tang Zhu ◽  
Michela Bossolasco ◽  
Martin Leduc ◽  
...  
Keyword(s):  
G Protein ◽  
Cell Nucleus ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Cell Metabolism ◽  
Hormone Secretion ◽  
G Protein Coupled Receptors ◽  
A Cell ◽  
G Protein Coupled

G-protein-coupled receptors (GPCRs) comprise a wide family of monomeric heptahelical glycoproteins that recognize a broad array of extracellular mediators including cationic amines, lipids, peptides, proteins, and sensory agents. Thus far, much attention has been given towards the comprehension of intracellular signaling mechanisms activated by cell membrane GPCRs, which convert extracellular hormonal stimuli into acute, non-genomic (e.g., hormone secretion, muscle contraction, and cell metabolism) and delayed, genomic biological responses (e.g., cell division, proliferation, and apoptosis). However, with respect to the latter response, there is compelling evidence for a novel intracrine mode of genomic regulation by GPCRs that implies either the endocytosis and nuclear translocation of peripheral-liganded GPCR and (or) the activation of nuclearly located GPCR by endogenously produced, nonsecreted ligands. A noteworthy example of the last scenario is given by heptahelical receptors that are activated by bioactive lipoids (e.g., PGE2 and PAF), many of which may be formed from bilayer membranes including those of the nucleus. The experimental evidence for the nuclear localization and signalling of GPCRs will be reviewed. We will also discuss possible molecular mechanisms responsible for the atypical compartmentalization of GPCRs at the cell nucleus, along with their role in gene expression.

Vitamin K epoxide reductase significantly improves carboxylation in a cell line overexpressing factor X

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3811-3815 ◽  
Author(s):  
Yan-Mei Sun ◽  
Da-Yun Jin ◽  
Rodney M. Camire ◽  
Darrel W. Stafford
Keyword(s):  
Binding Site ◽  
Cell Line ◽  
Vitamin K ◽  
Turnover Rate ◽  
Factor X ◽  
Vitamin K Epoxide Reductase ◽  
Transfected Cells ◽  
Epoxide Reductase ◽  
A Cell ◽  
Practical Implications

Previously we reported that we could increase the fraction of carboxylated factor X by reducing the affinity of the propeptide for its binding site on human gamma glutamyl carboxylase. We attributed this to an increased turnover rate. However, even with the reduced affinity propeptide, when sufficient overproduction of factor X is achieved, there is still a significant fraction of uncarboxylated recombinant factor X. We report here that the factor X of such a cell line was only 52% carboxylated but that the fraction of carboxylated factor X could be increased to 92% by coexpressing the recently identified gene for vitamin K epoxide reductase. Because vitamin K is in excess in both the untransfected and vitamin K epoxide reductase (VKOR)–transfected cells, the simplest explanation for this result is that VKOR catalyzes both the reduction of vitamin K epoxide to vitamin K and the conversion of vitamin K to vitamin K hydroquinone. In addition to its mechanistic relevance, this observation has practical implications for overproducing recombinant vitamin K–dependent proteins for therapeutic use.

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