Sodium Pump Research Articles

A Historical Reflection on Scientific Advances in Understanding Thyroid Hormone Action.

Background: Thyroid hormone (TH) has actions in every tissue of the body and is essential for normal development, as well as having important actions in the adult. The earliest markers of TH action that were identified and monitored clinically, even before TH could be measured in serum, included oxygen consumption, basal metabolic rate, serum cholesterol, and deep tendon reflex time. Cellular, rodent, amphibian, zebrafish, and human models have been used to study TH action. Summary: Early studies of the mechanism of TH action focused on saturable-specific triiodothyronine (T3) nuclear binding and direct actions of T3 that altered protein expression. Additional effects of TH were recognized on mitochondria, stimulation of ion transport, especially the sodium potassium ATPase, augmentation of adrenergic signaling, role as a neurotransmitter, and direct plasma membrane effects. The cloning of the thyroid hormone receptor (THR) genes in 1986 and report of the THR crystal structure in 1995 produced rapid progress in understanding the mechanism of TH nuclear action, as well as the development of modified THR ligands. These findings revealed nuances of TH signaling, including the role of nuclear receptor coactivators and corepressors, repression of positively stimulated genes by the unliganded receptor, THR isoform-specific actions of TRα (THRA) and TRβ (THRB), and THR binding DNA as a heterodimer with retinoid-x-receptor (RXR) for genes positively regulated by TH. The identification of genetic disorders of TH transport and signaling, especially Resistance to Thyroid Hormone (RTH) and monocarboxylate transporter 8 (Mct8) defects, has been highly informative with respect to the mechanism of TH action. Conclusions: The impact of THR isoform, post-translational modifications, receptor cofactors, DNA response element, and selective TH tissue uptake, on TH action, have clinical implications for diagnosing and treating thyroid disease. Additionally, these findings have led to the development of novel TH and TH analogue therapies for metabolic, neurological, and cardiovascular diseases.

Biological rhythms are correlated with Na+, K+-ATPase and oxidative stress biomarkers: A translational study on bipolar disorder

BackgroundBipolar disorder (BD) is a chronic, severe, and multifactorial psychiatric disorder. Although biological rhythms alterations, sodium potassium pump (Na+, K+-ATPase) changes, and oxidative stress appear to play a critical role in the etiology and pathophysiology of BD, the inter-connection between them has not been described. Therefore this study evaluated the association between biological rhythms, Na+, K+-ATPase, and oxidative stress parameters in BD patients and the preclinical paradoxical sleep deprivation model (PSD). MethodsA translational study was conducted, including a case-control protocol with 36 BD and 46 healthy controls (HC). Subjects completed the Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN). In addition, Erythrocyte Na+, K+-ATPase activity, and oxidative and nitrosative stress markers were assessed (4-hydroxynonenal [4-HNE], 8-isoprostane [8-ISO], thiobarbituric acid reactive substances [TBARS], carbonyl, 3-nitrotyrosine [3-nitro]). In the preclinical protocol, the same biomarkers were evaluated in the frontal cortex, hippocampus, and striatum from mice submitted to the PSD. ResultsBD patients had a significantly higher total score of BRIAN versus HCs. Additionally, individuals with BD showed decreased Na+, K+-ATPase activity and increased oxidative stress parameters compared to HC without psychiatric disorders. This difference was driven by actively depressed BD subjects. The mice submitted to the PSD also demonstrated decreased Na+, K+-ATPase activity and increased oxidative stress parameters. LimitationsBRIAN biological underpinning is less well characterized; We did not control for medication status; Sample size is limited; PSD it is not a true model of BD. ConclusionsThe present study found a significant correlation between Na+, K+-ATPase and oxidative stress with changes in biological rhythms, reinforcing the importance of these parameters to BD.

Light-Driven Chloride and Sulfate Pump with Two Different Transport Modes.

Ion pumps are membrane proteins that actively translocate ions by using energy. All known pumps bind ions in the resting state, and external energy allows ion transport through protein structural changes. The light-driven sodium-ion pump Krokinobacter eikastus rhodopsin 2 (KR2) is an exceptional case in which ion binding follows the energy input. In this study, we report another case of this unusual transport mode. The NTQ rhodopsin from Alteribacter aurantiacus (AaClR) is a natural light-driven chloride pump, in which the chloride ion binds to the resting state. AaClR is also able to pump sulfate ions, though the pump efficiency is much lower for sulfate ions than for chloride ions. Detailed spectroscopic analysis revealed no binding of the sulfate ion to the resting state of AaClR, indicating that binding of the substrate (sulfate ion) to the resting state is not necessary for active transport. This property of the AaClR sulfate pump is similar to that of the KR2 sodium pump. Photocycle dynamics of the AaClR sulfate pump resemble a non-functional cycle in the absence of anions. Despite this, flash photolysis and difference Fourier transform infrared spectroscopy suggest transient binding of the sulfate ion to AaClR. The molecular mechanism of this unusual active transport by AaClR is discussed.

Evaluation of In-vitro Antioxidant Potential of Bryophillum pinnatum Leaf Juice in Phenyl Hydrazine Treated Goat Erythrocytes

Phytochemicals are known to contain a high concentration of therapeutically active principles, which, when consumed in sufficient quantities, can have drug-like effects. Bryophillum pinnatum (Lam.) is a succulent-ethno medicinal xerophyte with a long history of use in traditional Indian medicine. Because reactive oxygen species are the most common etiological factor in many degenerative diseases, controlling them with antioxidants may both treat and prevent disease progression. The current study will look at the ability of fresh leaf juice of Bryophillum pinnatum (Lam.) (FLJBP) to prevent oxidative injury and subsequent hemolysis in goat erythrocytes as a model test system. The catalytic activity of membrane bound enzymes like sodium potassium-ATPase, Ach-Ease, and metabolic enzymes like hexokinase, as well as the NO concentration in goat RBCs, were measured. Phenyl hydrazine was used first, followed by FLJBP at concentrations of 20, 40, 60, 80, and 100g/ml. A dose-dependent (PHZ) increase in Pi liberation by hexokinase and Na+/K+ ATPase, as well as increased formation of thiocholine iodide and enhanced NO scavenging potential, has indicated that flip has good anti-oxidant and anti-haemolytic activity. To record the functional food status of Bryophillum pinnatum (Lam.) species, a more rigorous and stringent battery of pharmacological, phytochemical, and bio analytical studies, followed by observational studies in humans, will be conducted.

Silencing of ATP1A1 attenuates cell membrane disruption by nanosecond electric pulses

This study explored the role of the Na/K-ATPase (NKA) in membrane permeabilization induced by nanosecond electric pulses. Using CRISPR/Cas9 and shRNA, we silenced the ATP1A1 gene, which encodes α1 NKA subunit in U937 human monocytes. Silencing reduced the rate and the cumulative uptake of YoPro-1 dye after electroporation by 300-ns, 7–10 kV/cm pulses, while ouabain, a specific NKA inhibitor, enhanced YoPro-1 entry. We conclude that the α1 subunit supports the electropermeabilized membrane state, by forming or stabilizing electropores or by hindering repair mechanisms, and this role is independent of NKA's ion pump function.

Structure of the Blood Brain Barrier and its Role in the Transporters for the Movement of Substrates across the Barriers.

For the brain to operate normally and to develop with structural integrity in addition to neuronal function, blood-brain barrier present in brain capillaries serves as a vital barrier mechanism. In addition to the transport barrier created by membranes, transporters, and vesicular processes, the structure and function of the BBB are summarised. The physical barrier is created by endothelial tight junctions. The permeability and transport of molecules between extracellular fluid and plasma are constrained by the presence of tight junctions between neighbouring endothelial cells. Each solute must pass through both membranes in the luminal and abluminal divisions. The functions of the neurovascular unit are described, with special emphasis on the pericytes, microglia, and astrocyte endfeet. The luminal membrane contains five separate facilitative transport mechanisms, each of which is exclusive to a few substrates. Nevertheless, the import of big-branched and aromatic neutral amino acids is facilitated by two key carriers (System L and y+) in the plasma membrane. It is asymmetrically present in both membranes. The sodium pump Na+/K+-ATPase is highly expressed in the abluminal membrane, where many Na+ dependent transport mechanisms move amino acids against its concentration gradient. The trojan horse strategy, which uses molecular tools to bind the medication and its formulations, is also preferred in drug delivery. The BBB's cellular structure, the transport systems unique to each substrate, and the necessity to identify transporters with changes that assist the transfer of various medications have all been changed in the current work. Nevertheless, to rule out the BBB passage for the new class of neuroactive medications, the mixing of traditional pharmacology and nanotechnology needs to be focused on outcomes that show promise.

Ian Michael Glynn. 3 June 1928—7 July 2022

In the mid 1950s the convergence of crucial discoveries on nerve and muscle physiology brought to centre stage the question of how sodium and potassium concentration gradients needed for nerve conduction and muscle contraction are maintained. This was the subject Ian Glynn set out to investigate when he returned to Cambridge as a Trinity College graduate student in 1953. His initial results on the sodium and potassium permeabilities of the human red blood cell membrane, published in 1956–1967, established these cells as an ideal experimental system for studying the transport properties of the ‘sodium pump’ because of the ease with which the ionic composition of intra- and extracellular environments could be controlled, cell metabolism managed and ionic fluxes measured using isotopes. This work was followed by ground-breaking contributions from his research group over the next decades in a long series of brilliantly designed experiments, setting the foundations of our current understanding of the molecular mechanism of the sodium/potassium pump. Ian became a Trinity College fellow in 1960, advanced rapidly to a professorship in the Department of Physiology after being elected Fellow of the Royal Society in 1970, and was appointed head of department in 1986 until his retirement in 1995.

Resting membrane state as an interplay of electrogenic transporters with various pumps.

In this study, a new idea that electrogenic transporters determine cell resting state is presented. The previous assumption was that pumps, especially the sodium one, determine it. The latter meets difficulties, because it violates the law of conservation of energy; also a significant deficit of pump activity is reported. The amount of energy carried by a single ATP molecule reflects the potential of the inner mitochondrial membrane, which is about -200 mV. If pumps enforce a resting membrane potential that is more than twice smaller, then the majority of energy stored in ATP would be dissipated by each pump turning. However, this problem could be solved if control is transferred from pumps to something else, e.g., electrogenic transporters. Then pumps would transfer the energy to the ionic gradient without losses, while the cell surface membrane potential would be associated with the reversal potential of some electrogenic transporters. A minimal scheme of this type would include a sodium-calcium exchanger as well as sodium and calcium pumps. However, note that calcium channels and pumps are positioned along both intracellular organelles and the surface membrane. Therefore, the above-mentioned scheme would involve them as well as possible intercellular communications. Such schemes where various kinds of pumps are assumed to work in parallel may explain, to a great extent, the slow turning rate of the individual members. Interaction of pumps and transporters positioned at distant biological membranes with various forms of energy transfer between them may thus result in hypoxic/reperfusion injury, different kinds of muscle fatigue, and nerve-glia interactions.

Bio-Inspired Design of Superconducting Spiking Neuron and Synapse.

The imitative modelling of processes in the brain of living beings is an ambitious task. However, advances in the complexity of existing hardware brain models are limited by their low speed and high energy consumption. A superconducting circuit with Josephson junctions closely mimics the neuronal membrane with channels involved in the operation of the sodium-potassium pump. The dynamic processes in such a system are characterised by a duration of picoseconds and an energy level of attojoules. In this work, two superconducting models of a biological neuron are studied. New modes of their operation are identified, including the so-called bursting mode, which plays an important role in biological neural networks. The possibility of switching between different modes in situ is shown, providing the possibility of dynamic control of the system. A synaptic connection that mimics the short-term potentiation of a biological synapse is developed and demonstrated. Finally, the simplest two-neuron chain comprising the proposed bio-inspired components is simulated, and the prospects of superconducting hardware biosimilars are briefly discussed.

The Na+,K+-ATPase and its stoichiometric ratio: some thermodynamic speculations.

Almost seventy years after its discovery, the sodium-potassium adenosine triphosphatase (the sodium pump) located in the cell plasma membrane remains a source of novel mechanistic and physiologic findings. A noteworthy feature of this enzyme/transporter is its robust stoichiometric ratio under physiological conditions: it sequentially counter-transports three sodium ions and two potassium ions against their electrochemical potential gradients per each hydrolyzed ATP molecule. Here we summarize some present knowledge about the sodium pump and its physiological roles, and speculate whether energetic constraints may have played a role in the evolutionary selection of its characteristic stoichiometric ratio.

New Insights on the Role of Marinobufagenin from Bench to Bedside in Cardiovascular and Kidney Diseases.

Marinobufagenin (MBG) is a member of the bufadienolide family of compounds, which are natural cardiac glycosides found in a variety of animal species, including man, which have different physiological and biochemical functions but have a common action on the inhibition of the adenosine triphosphatase sodium-potassium pump (Na+/K+-ATPase). MBG acts as an endogenous cardiotonic steroid, and in the last decade, its role as a pathogenic factor in various human diseases has emerged. In this paper, we have collated major evidence regarding the biological characteristics and functions of MBG and its implications in human pathology. This review focused on MBG involvement in chronic kidney disease, including end-stage renal disease, cardiovascular diseases, sex and gender medicine, and its actions on the nervous and immune systems. The role of MBG in pathogenesis and the development of a wide range of pathological conditions indicate that this endogenous peptide could be used in the future as a diagnostic biomarker and/or therapeutic target, opening important avenues of scientific research.

Oxidative brain and cerebellum injury in diabetes and prostate cancer model: Protective effect of metformin.

The body can host the spread of prostate cancer cells. Metastases from prostate cancer are more frequently seen in the brain, liver, lungs, and lymph nodes. A well-known antidiabetic drug, metformin, is also known to have antitumor effects. Our study focuses on the evaluation of potential metformin protective effects on brain and cerebellum damage in streptozotocin (STZ)-induced diabetic and Dunning prostate cancer models. In this investigation, six groups of male Copenhagen rats were created: control, diabetic (D), cancer (C), diabetic + cancer (DC), cancer + metformin, and diabetic + cancer + metformin. The brain and cerebellum tissues of the rats were taken after sacrifice. Oxidative stress markers including reduced glutathione level, lipid peroxidation, glutathione reductase, glutathione peroxidase, glutathione-S-transferase, catalase, superoxide dismutase activities, reactive oxygen species, total oxidant and total antioxidant status, lactate dehydrogenase, xanthine oxidase, acetylcholinesterase activities, protein carbonyl contents, nitric oxide and OH-proline levels, sodium potassium ATPase, carbonic anhydrase, and glucose-6-phosphate dehydrogenase activities; glycoprotein levels including hexose, hexosamine, fucose, and sialic acid levels; and histone deacetylase activity as a cancer marker were determined. Oxidative stress markers were impaired and glycoprotein levels and histone deacetylase activity were increased in the D, C, and DC groups. Metformin therapy reversed these effects. Metformin was found to protect the brain and cerebellum of STZ-induced diabetic rats with Dunning prostate cancer from harm caused by MAT-Lylu metastatic cells.

Comparison of toxicity of silver nanomaterials and silver nitrate on developing zebrafish embryos: Bioavailability, osmoregulatory and oxidative stress

The mechanisms of toxicity of engineered nanomaterials (ENMs) to the early life stages of freshwater fish, and the relative hazard compared to dissolved metals, is only partially understood. In the present study, zebrafish (Danio rerio) embryos were exposed to lethal concentrations of silver nitrate (AgNO3) or silver (Ag) ENMs (primary size 42.5 ± 10.2 nm). The 96 h-LC50 for AgNO3 was 32.8 ± 0.72 μg Ag L−1 (mean ± 95% CI) compared to 6.5 ± 0.4 mg L−1 of the whole material for Ag ENMs; with the ENMs being orders of magnitude less toxic than the metal salt. The EC50 for hatching success was 30.5 ± 1.4 μg Ag L−1 and 6.04 ± 0.4 mg L−1 for AgNO3 and Ag ENMs, respectively. Further sub-lethal exposures were performed with the estimated LC10 concentrations for both AgNO3 or Ag ENMs over 96 h, where about 3.7% of the total Ag as AgNO3 was internalised, as measured by Ag accumulation in the dechorionated embryos. However, for the ENM exposures, nearly all (99.8%) of the total Ag was associated with chorion; indicating the chorion as an effective barrier to protect the embryo in the short term. Calcium (Ca2+) and sodium (Na+) depletion was induced in embryos by both forms of Ag, but hyponatremia was more pronounced in the nano form. Total glutathione (tGSH) levels declined in embryos exposed to both Ag forms, but a superior depletion occurred with the nano form. Nevertheless, oxidative stress was mild as superoxide dismutase (SOD) activity stayed uniform and the sodium pump (Na+/K+-ATPase) activity had no appreciable inhibition compared to the control. In conclusion, AgNO3 was more toxic to the early life stage zebrafish than the Ag ENMs, still differences were found in the exposure and toxic mechanisms of both Ag forms.

Silencing of PKG1 Gene Mimics Effect of Aging and Sensitizes Rat Vascular Smooth Muscle Cells to Cardiotonic Steroids: Impact on Fibrosis and Salt Sensitivity.

Background Marinobufagenin, NKA (Na/K-ATPase) inhibitor, causes vasoconstriction and induces fibrosis via inhibition of Fli1 (Friend leukemia integration-1), a negative regulator of collagen synthesis. In vascular smooth muscle cells (VSMC), ANP (atrial natriuretic peptide), via a cGMP/PKG1 (protein kinase G1)-dependent mechanism, reduces NKA sensitivity to marinobufagenin. We hypothesized that VSMCfrom old rats, due to downregulation of ANP/cGMP/PKG-dependent signaling, would exhibit heightened sensitivity to the profibrotic effect of marinobufagenin. Methods and Results Cultured VSMCfrom the young (3-month-old) and old (24-month-old) male Sprague-Dawley rats and young VSMCwith silenced PKG1 gene were treated with 1 nmol/L ANP, or with 1 nmol/L marinobufagenin, or with a combination of ANP and marinobufagenin. Collagen-1, Fli1, and PKG1 levels were assessed by Western blotting analyses. Vascular PKG1 and Fli1 levels in the old rats were reduced compared with their young counterparts. ANP prevented inhibition of vascular NKA by marinobufagenin in young VSMC but not in old VSMC. In VSMC from the young rats, marinobufagenin induced downregulation of Fli1 and an increase in collagen-1 level, whereas ANP blocked this effect. Silencing of the PKG1 gene in young VSMC resulted in a reduction in levels of PKG1 and Fli1; marinobufagenin additionally reduced Fli1 and increased collagen-1 level, and ANP failed to oppose these marinobufagenin effects, similar to VSMC from the old rats with the age-associated reduction in PKG1. Conclusions Age-associated reduction in vascular PKG1 and the resultant decline in cGMP signaling lead to the loss of the ability of ANP to oppose marinobufagenin-induced inhibition of NKA and fibrosis development. Silencing of the PKG1 gene mimicked these effects of aging.

Coevolutionary escalation led to differentially adapted paralogs of an insect's Na,K-ATPase optimizing resistance to host plant toxins.

Cardiac glycosides are chemical defence toxins known to fatally inhibit the Na,K-ATPase (NKA) throughout the animal kingdom. Several animals, however, have evolved target-site insensitivity through substitutions in the otherwise highly conserved cardiac glycoside binding pocket of the NKA. The large milkweed bug, Oncopeltus fasciatus, shares a long evolutionary history with cardiac glycoside containing plants that led to intricate adaptations. Most strikingly, several duplications of the bugs' NKA1α gene provided the opportunity for differential resistance-conferring substitutions and subsequent sub-functionalization of the enzymes. Here, we analysed cardiac glycoside resistance and ion pumping activity of nine functional NKA α/β-combinations of O. fasciatus expressed in cell culture. We tested the enzymes with two structurally distinct cardiac glycosides, calotropin, a host plant compound, and ouabain, a standard cardiac glycoside. The identity and number of known resistance-conferring substitutions in the cardiac glycoside binding site significantly impacted activity and toxin resistance in the three α-subunits. The β-subunits also influenced the enzymes' characteristics, yet to a lesser extent. Enzymes containing the more ancient αC-subunit were inhibited by both compounds but much more strongly by the host plant toxin calotropin than by ouabain. The sensitivity to calotropin was diminished in enzymes containing the more derived αB and αA, which were only marginally inhibited by both cardiac glycosides. This trend culminated in αAβ1 having higher resistance against calotropin than against ouabain. These results support the coevolutionary escalation of plant defences and herbivore tolerance mechanisms. The possession of multiple paralogs additionally mitigates pleiotropic effects by compromising between ion pumping activity and resistance.

Dietary magnesium chelate alleviates oxidative stress and improves growth in white-leg shrimp, Penaeus vannamei (Boone, 1931), reared in inland saline water

Nine semi-purified diets containing either magnesium citrate (MgC) levels of 0.0, 2.24, 4.48, 6.72, 8.96 g Kg-1 or magnesium amino acid complex (MgAA) levels of 2.17, 4.35, 6.52, 8.7 g Kg-1 were fed to P. vannamei juveniles thrice daily and reared for 60 days in sub-optimum inland saline ground water (ISGW) of 10‰. Five hundred sixty-seven healthy juvenile shrimps (3.51 ± 0.03 g) were randomly stocked in triplicate into 350 L tanks at a density of 60 m-3. The weight gain (WG %) and specific growth rate were highest in the shrimps fed with 4.48 g Kg-1 MgC and 2.17 g Kg-1 MgAA. Further increase in the dietary magnesium did not show any additional growth, relatively inhibited it. The positive correlations (p < 0.01) between WG % and magnesium contents of serum, body and hepatopancreas suggests indirect involvement of tissue magnesium in growth performance. Conversely, negative correlations (p < 0.01) of WG % with superoxide dismutase and heat shock protein 70 (HSP 70) in gill and hepatopancreas indicate stress-induced inhibition of growth. Higher inclusion of dietary magnesium altered sodium-potassium ATPase (NKA) mRNA expression in hepatopancreas. The minimum dietary MgC and MgAA supplementations of P. vannamei juveniles for growth improvement were determined to be 4.25 g Kg-1 and 2.38 g Kg-1 feed, respectively, which was equivalent to 2.86 g Kg-1 and 1.64 g Kg-1 feed respectively, using broken-line regression analysis based on the weight gain (%). Overall results reveal that dietary MgAA was better than MgC in alleviating ionic stress and improving growth performance and survival rate in shrimp reared in 10‰ ISGW of the sub-optimum magnesium suite.

Genome sequence of Ophryocystis elektroscirrha, an apicomplexan parasite of monarch butterflies: cryptic diversity and response to host-sequestered plant chemicals

Apicomplexa are ancient and diverse organisms which have been poorly characterized by modern genomics. To better understand the evolution and diversity of these single-celled eukaryotes, we sequenced the genome of Ophryocystis elektroscirrha, a parasite of monarch butterflies, Danaus plexippus. We contextualize our newly generated resources within apicomplexan genomics before answering longstanding questions specific to this host-parasite system. To start, the genome is miniscule, totaling only 9 million bases and containing fewer than 3,000 genes, half the gene content of two other sequenced invertebrate-infecting apicomplexans, Porospora gigantea and Gregarina niphandrodes. We found that O. elektroscirrha shares different orthologs with each sequenced relative, suggesting the true set of universally conserved apicomplexan genes is very small indeed. Next, we show that sequencing data from other potential host butterflies can be used to diagnose infection status as well as to study diversity of parasite sequences. We recovered a similarly sized parasite genome from another butterfly, Danaus chrysippus, that was highly diverged from the O. elektroscirrha reference, possibly representing a distinct species. Using these two new genomes, we investigated potential evolutionary response by parasites to toxic phytochemicals their hosts ingest and sequester. Monarch butterflies are well-known to tolerate toxic cardenolides thanks to changes in the sequence of their Type II ATPase sodium pumps. We show that Ophryocystis completely lacks Type II or Type 4 sodium pumps, and related proteins PMCA calcium pumps show extreme sequence divergence compared to other Apicomplexa, demonstrating new avenues of research opened by genome sequencing of non-model Apicomplexa.

Temporal dynamics of Na/K pump mediated memory traces: insights from conductance-based models of Drosophila neurons.

Sodium potassium ATPases (Na/K pumps) mediate long-lasting, dynamic cellular memories that can last tens of seconds. The mechanisms controlling the dynamics of this type of cellular memory are not well understood and can be counterintuitive. Here, we use computational modeling to examine how Na/K pumps and the ion concentration dynamics they influence shape cellular excitability. In a Drosophila larval motor neuron model, we incorporate a Na/K pump, a dynamic intracellular Na+ concentration, and a dynamic Na+ reversal potential. We probe neuronal excitability with a variety of stimuli, including step currents, ramp currents, and zap currents, then monitor the sub- and suprathreshold voltage responses on a range of time scales. We find that the interactions of a Na+-dependent pump current with a dynamic Na+ concentration and reversal potential endow the neuron with rich response properties that are absent when the role of the pump is reduced to the maintenance of constant ion concentration gradients. In particular, these dynamic pump-Na+ interactions contribute to spike rate adaptation and result in long-lasting excitability changes after spiking and even after sub-threshold voltage fluctuations on multiple time scales. We further show that modulation of pump properties can profoundly alter a neuron's spontaneous activity and response to stimuli by providing a mechanism for bursting oscillations. Our work has implications for experimental studies and computational modeling of the role of Na/K pumps in neuronal activity, information processing in neural circuits, and the neural control of animal behavior.

Casting a Wider Net When Fishing for Mechanisms of Anesthesia.

Casting a Wider Net When Fishing for Mechanisms of Anesthesia.

Unidirectional fluxes of monovalent ions in human erythrocytes compared with lymphoid U937 cells: Transient processes after stopping the sodium pump and in response to osmotic challenge.

Recently, we have developed software that allows, using a minimum of required experimental data, to find the characteristics of ion homeostasis and a list of all unidirectional fluxes of monovalent ions through the main pathways in the cell membrane both in a balanced state and during the transient processes. Our approach has been successfully validated in human proliferating lymphoid U937 cells during transient processes after stopping the Na/K pump by ouabain and for staurosporine-induced apoptosis. In present study, we used this approach to find the characteristics of ion homeostasis and the monovalent ion fluxes through the cell membrane of human erythrocytes in a resting state and during the transient processes after stopping the Na/K pump with ouabain and in response to osmotic challenge. Due to their physiological significance, erythrocytes remain the object of numerous studies, both experimental and computational methods. Calculations showed that, under physiological conditions, the K+ fluxes through electrodiffusion channels in the entire erythrocyte ion balance is small compared to the fluxes through the Na/K pump and cation-chloride cotransporters. The proposed computer program well predicts the dynamics of the erythrocyte ion balance disorders after stopping the Na/K pump with ouabain. In full accordance with predictions, transient processes in human erythrocytes are much slower than in proliferating cells such as lymphoid U937 cells. Comparison of real changes in the distribution of monovalent ions under osmotic challenge with the calculated ones indicates a change in the parameters of the ion transport pathways through the plasma membrane of erythrocytes in this case. The proposed approach may be useful in studying the mechanisms of various erythrocyte dysfunctions.