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Progress in Biophysics and Molecular... 2022This retrospective traces the hypothesis of ion channels from an early statement in a 1970 essay in this journal (Hille, B., 1970, Prog. Biophys. Mol. Biol. 21, 1-32) to... (Review)
Review
This retrospective traces the hypothesis of ion channels from an early statement in a 1970 essay in this journal (Hille, B., 1970, Prog. Biophys. Mol. Biol. 21, 1-32) to its realization today in biophysical, molecular, biochemical, and structural terms. The Na and K channels of the action potential have been isolated, reconstituted, cloned, mutated, and expressed. They are conformationally flexible, multi-pass glycosylated membrane proteins. Refined atomic structures of several conformational states are known. The discoveries over this half century history illustrate the growth of a field from initial ideas to a mature discipline of biology, physiology, and biomedical science.
Topics: Ion Channels; Ions; Potassium; Retrospective Studies; Sodium
PubMed: 34856230
DOI: 10.1016/j.pbiomolbio.2021.11.003 -
International Journal of Molecular... Apr 2018Ion channels activated by reactive oxygen species (ROS) have been found in the plasma membrane of charophyte , dicotyledon , and , and the monocotyledon . Their... (Review)
Review
Ion channels activated by reactive oxygen species (ROS) have been found in the plasma membrane of charophyte , dicotyledon , and , and the monocotyledon . Their activities have been reported in charophyte giant internodes, root trichoblasts and atrichoblasts, pollen tubes, and guard cells. Hydrogen peroxide and hydroxyl radicals are major activating species for these channels. Plant ROS-activated ion channels include inwardly-rectifying, outwardly-rectifying, and voltage-independent groups. The inwardly-rectifying ROS-activated ion channels mediate Ca-influx for growth and development in roots and pollen tubes. The outwardly-rectifying group facilitates K⁺ efflux for the regulation of osmotic pressure in guard cells, induction of programmed cell death, and autophagy in roots. The voltage-independent group mediates both Ca influx and K⁺ efflux. Most studies suggest that ROS-activated channels are non-selective cation channels. Single-channel studies revealed activation of 14.5-pS Ca influx and 16-pS K⁺ efflux unitary conductances in response to ROS. The molecular nature of ROS-activated Ca influx channels remains poorly understood, although annexins and cyclic nucleotide-gated channels have been proposed for this role. The ROS-activated K⁺ channels have recently been identified as products of Stellar K⁺ Outward Rectifier () and Guard cell Outwardly Rectifying K⁺ channel () genes.
Topics: Animals; Calcium Signaling; Humans; Hydroxyl Radical; Plants; Potassium; Reactive Oxygen Species
PubMed: 29690632
DOI: 10.3390/ijms19041263 -
Biophysical Journal Jun 2022Hyperpolarization-activated cyclic-nucleotide gated channels (HCNs) are responsible for the generation of pacemaker currents (I or I) in cardiac and neuronal cells....
Hyperpolarization-activated cyclic-nucleotide gated channels (HCNs) are responsible for the generation of pacemaker currents (I or I) in cardiac and neuronal cells. Despite the overall structural similarity to voltage-gated potassium (Kv) channels, HCNs show much lower selectivity for K over Na ions. This increased permeability to Na is critical to their role in membrane depolarization. HCNs can also select between Na and Li ions. Here, we investigate the unique ion selectivity properties of HCNs using molecular-dynamics simulations. Our simulations suggest that the HCN1 pore is flexible and dilated compared with Kv channels with only one stable ion binding site within the selectivity filter. We also observe that ion coordination and hydration differ within the HCN1 selectivity filter compared with those in Kv and cyclic-nucleotide gated channels. Additionally, the C358T mutation further stabilizes the symmetry of the binding site and provides a more fit space for ion coordination, particularly for Li.
Topics: Cyclic Nucleotide-Gated Cation Channels; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Ions; Nucleotides; Potassium; Potassium Channels; Sodium
PubMed: 35474263
DOI: 10.1016/j.bpj.2022.04.024 -
Current Protocols in Chemical Biology Sep 2019Vital cells maintain a steep potassium ion (K ) gradient across the plasma membrane. Intracellular potassium ion concentrations ([K ]) and especially the [K ] within the...
Vital cells maintain a steep potassium ion (K ) gradient across the plasma membrane. Intracellular potassium ion concentrations ([K ]) and especially the [K ] within the extracellular matrix are strictly regulated, the latter within a narrow range of ∼3.5 to 5.0 mM. Alterations of the extracellular K homeostasis are associated with severe pathological alterations and systemic diseases including hypo- or hypertension, heart rate alterations, heart failure, neuronal damage or abnormal skeleton muscle function. In higher eukaryotic organisms, the maintenance of the extracellular [K ] is mainly achieved by the kidney, responsible for K excretion and reabsorption. Thus, renal dysfunctions are typically associated with alterations in serum- or plasma [K ]. Generally, [K ] quantifications within bodily fluids are performed using ion selective electrodes. However, tracking such alterations in experimental models such as mice features several difficulties, mainly due to the small blood volume of these animals, hampering the repetitive collection of sample volumes required for measurements using ion selective electrodes. We have recently developed highly sensitive, genetically encoded potassium ion indicators, the GEPIIs, applicable for in vitro determinations of [K ]. In addition to the determination of [K ] within bodily fluids, GEPIIs proved suitable for the real-time visualization of cell viability over time and the exact determination of the number of dead cells. © 2019 The Authors.
Topics: Animals; Body Fluids; Cell Line, Tumor; Cell Survival; Fluorescence Resonance Energy Transfer; Glucose; Ions; Mice; Plasmids; Potassium; Recombinant Proteins
PubMed: 31483097
DOI: 10.1002/cpch.71 -
The Journal of Biological Chemistry Sep 2016Regulation of enzymes through metal ion complexation is widespread in biology and underscores a physiological need for stability and high catalytic activity that likely... (Review)
Review
Regulation of enzymes through metal ion complexation is widespread in biology and underscores a physiological need for stability and high catalytic activity that likely predated proteins in the RNA world. In addition to divalent metals such as Ca, Mg, and Zn, monovalent cations often function as efficient and selective promoters of catalysis. Advances in structural biology unravel a rich repertoire of molecular mechanisms for enzyme activation by Na and K Strategies range from short-range effects mediated by direct participation in substrate binding, to more distributed effects that propagate long-range to catalytic residues. This review addresses general considerations and examples.
Topics: Catalysis; Cations, Monovalent; Enzymes; Potassium; Sodium
PubMed: 27462078
DOI: 10.1074/jbc.R116.737833 -
Journal of the American Society of... Jun 2023Rapid renal responses to ingested potassium are essential to prevent hyperkalemia and also play a central role in blood pressure regulation. Although local extracellular...
SIGNIFICANCE STATEMENT
Rapid renal responses to ingested potassium are essential to prevent hyperkalemia and also play a central role in blood pressure regulation. Although local extracellular K + concentration in kidney tissue is increasingly recognized as an important regulator of K + secretion, the underlying mechanisms that are relevant in vivo remain controversial. To assess the role of the signaling kinase mTOR complex-2 (mTORC2), the authors compared the effects of K + administered by gavage in wild-type mice and knockout mice with kidney tubule-specific inactivation of mTORC2. They found that mTORC2 is rapidly activated to trigger K + secretion and maintain electrolyte homeostasis. Downstream targets of mTORC2 implicated in epithelial sodium channel regulation (SGK1 and Nedd4-2) were concomitantly phosphorylated in wild-type, but not knockout, mice. These findings offer insight into electrolyte physiologic and regulatory mechanisms.
BACKGROUND
Increasing evidence implicates the signaling kinase mTOR complex-2 (mTORC2) in rapid renal responses to changes in plasma potassium concentration [K + ]. However, the underlying cellular and molecular mechanisms that are relevant in vivo for these responses remain controversial.
METHODS
We used Cre-Lox-mediated knockout of rapamycin-insensitive companion of TOR (Rictor) to inactivate mTORC2 in kidney tubule cells of mice. In a series of time-course experiments in wild-type and knockout mice, we assessed urinary and blood parameters and renal expression and activity of signaling molecules and transport proteins after a K + load by gavage.
RESULTS
A K + load rapidly stimulated epithelial sodium channel (ENaC) processing, plasma membrane localization, and activity in wild-type, but not in knockout, mice. Downstream targets of mTORC2 implicated in ENaC regulation (SGK1 and Nedd4-2) were concomitantly phosphorylated in wild-type, but not knockout, mice. We observed differences in urine electrolytes within 60 minutes, and plasma [K + ] was greater in knockout mice within 3 hours of gavage. Renal outer medullary potassium (ROMK) channels were not acutely stimulated in wild-type or knockout mice, nor were phosphorylation of other mTORC2 substrates (PKC and Akt).
CONCLUSIONS
The mTORC2-SGK1-Nedd4-2-ENaC signaling axis is a key mediator of rapid tubule cell responses to increased plasma [K + ] in vivo . The effects of K + on this signaling module are specific, in that other downstream mTORC2 targets, such as PKC and Akt, are not acutely affected, and ROMK and Large-conductance K + (BK) channels are not activated. These findings provide new insight into the signaling network and ion transport systems that underlie renal responses to K +in vivo .
Topics: Mice; Animals; Phosphorylation; Potassium; Epithelial Sodium Channels; Protein Serine-Threonine Kinases; Potassium, Dietary; TOR Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Immediate-Early Proteins; Mechanistic Target of Rapamycin Complex 2; Kidney; Carrier Proteins; Mice, Knockout; Ion Transport
PubMed: 36890646
DOI: 10.1681/ASN.0000000000000109 -
The Journal of General Physiology Oct 2021The ability to discriminate between different ionic species, termed ion selectivity, is a key feature of ion channels and forms the basis for their physiological...
The ability to discriminate between different ionic species, termed ion selectivity, is a key feature of ion channels and forms the basis for their physiological function. Members of the degenerin/epithelial sodium channel (DEG/ENaC) superfamily of trimeric ion channels are typically sodium selective, but to a surprisingly variable degree. While acid-sensing ion channels (ASICs) are weakly sodium selective (sodium:potassium ratio ∼10:1), ENaCs show a remarkably high preference for sodium over potassium (>500:1). This discrepancy may be expected to originate from differences in the pore-lining second transmembrane segment (M2). However, these show a relatively high degree of sequence conservation between ASICs and ENaCs, and previous functional and structural studies could not unequivocally establish that differences in M2 alone can account for the disparate degrees of ion selectivity. By contrast, surprisingly little is known about the contributions of the first transmembrane segment (M1) and the preceding pre-M1 region. In this study, we used conventional and noncanonical amino acid-based mutagenesis in combination with a variety of electrophysiological approaches to show that the pre-M1 and M1 regions of mASIC1a channels are major determinants of ion selectivity. Mutational investigations of the corresponding regions in hENaC show that these regions contribute less to ion selectivity, despite affecting ion conductance. In conclusion, our work suggests that the remarkably different degrees of sodium selectivity in ASICs and ENaCs are achieved through different mechanisms. These results further highlight how M1 and pre-M1 are likely to differentially affect pore structure in these related channels.
Topics: Acid Sensing Ion Channels; Epithelial Sodium Channels; Ions; Potassium; Sodium
PubMed: 34436511
DOI: 10.1085/jgp.202112899 -
Nucleic Acids Research Jul 2014We present a new method for analyzing ion, or molecule, distributions around helical nucleic acids and illustrate the approach by analyzing data derived from molecular...
We present a new method for analyzing ion, or molecule, distributions around helical nucleic acids and illustrate the approach by analyzing data derived from molecular dynamics simulations. The analysis is based on the use of curvilinear helicoidal coordinates and leads to highly localized ion densities compared to those obtained by simply superposing molecular dynamics snapshots in Cartesian space. The results identify highly populated and sequence-dependent regions where ions strongly interact with the nucleic and are coupled to its conformational fluctuations. The data from this approach is presented as ion populations or ion densities (in units of molarity) and can be analyzed in radial, angular and longitudinal coordinates using 1D or 2D graphics. It is also possible to regenerate 3D densities in Cartesian space. This approach makes it easy to understand and compare ion distributions and also allows the calculation of average ion populations in any desired zone surrounding a nucleic acid without requiring references to its constituent atoms. The method is illustrated using microsecond molecular dynamics simulations for two different DNA oligomers in the presence of 0.15 M potassium chloride. We discuss the results in terms of convergence, sequence-specific ion binding and coupling with DNA conformation.
Topics: Chlorides; DNA; Ions; Molecular Dynamics Simulation; Nucleic Acid Conformation; Phosphorus; Potassium
PubMed: 24906882
DOI: 10.1093/nar/gku504 -
Metal Ions in Life Sciences 2016The two alkali cations Na(+) and K(+) have similar relative abundances in the earth crust but display very different distributions in the biosphere. In all living...
The two alkali cations Na(+) and K(+) have similar relative abundances in the earth crust but display very different distributions in the biosphere. In all living organisms, K(+) is the major inorganic cation in the cytoplasm, where its concentration (ca. 0.1 M) is usually several times higher than that of Na(+). Accumulation of Na(+) at high concentrations in the cytoplasm results in deleterious effects on cell metabolism, e.g., on photosynthetic activity in plants. Thus, Na(+) is compartmentalized outside the cytoplasm. In plants, it can be accumulated at high concentrations in vacuoles, where it is used as osmoticum. Na(+) is not an essential element in most plants, except in some halophytes. On the other hand, it can be a beneficial element, by replacing K(+) as vacuolar osmoticum for instance. In contrast, K(+) is an essential element. It is involved in electrical neutralization of inorganic and organic anions and macromolecules, pH homeostasis, control of membrane electrical potential, and the regulation of cell osmotic pressure. Through the latter function in plants, it plays a role in turgor-driven cell and organ movements. It is also involved in the activation of enzymes, protein synthesis, cell metabolism, and photosynthesis. Thus, plant growth requires large quantities of K(+) ions that are taken up by roots from the soil solution, and then distributed throughout the plant. The availability of K(+) ions in the soil solution, slowly released by soil particles and clays, is often limiting for optimal growth in most natural ecosystems. In contrast, due to natural salinity or irrigation with poor quality water, detrimental Na(+) concentrations, toxic for all crop species, are present in many soils, representing 6 % to 10 % of the earth's land area. Three families of ion channels (Shaker, TPK/KCO, and TPC) and 3 families of transporters (HAK, HKT, and CPA) have been identified so far as contributing to K(+) and Na(+) transport across the plasmalemma and internal membranes, with high or low ionic selectivity. In the model plant Arabidopsis thaliana, these families gather at least 70 members. Coordination of the activities of these systems, at the cell and whole plant levels, ensures plant K(+) nutrition, use of Na(+) as a beneficial element, and adaptation to saline conditions.
Topics: Carrier Proteins; Cations; Gene Expression Regulation, Plant; Homeostasis; Ion Channels; Plant Proteins; Plants; Potassium; Sodium; Soil; Water
PubMed: 26860305
DOI: 10.1007/978-3-319-21756-7_9 -
International Journal of Molecular... Nov 2023Ternary glassy electrolytes containing KS as a glass modifier and PS as a network former are synthesized by introducing a new type of complex and asymmetric salt,...
Ternary glassy electrolytes containing KS as a glass modifier and PS as a network former are synthesized by introducing a new type of complex and asymmetric salt, potassium triflate (KOTf), to obtain unprecedented K ion conductivity at ambient temperature. The glasses are synthesized using a conventional quenching technique at a low temperature. In general, alkali ionic glassy electrolytes of ternary systems, specifically for Li and Na ion conductivity, have been studied with the addition of halide salts or oxysalts such as MSO, MSiO, MPO (M = Li or Na), etc. We introduce a distinct and complex salt, potassium triflate (KOTf) with asymmetric anion, to the conventional glass modifier and former to synthesize K-ion-conducting glassy electrolytes. Two series of glassy electrolytes with a ternary system of (0.9-x)KS-xPS-0.1KOTf (x = 0.15, 0.30, 0.45, 0.60, and 0.75) and z(KS-2PS)-yKOTf (y = 0.05, 0.10, 0.15, 0.20, and 0.25) on a straight line of z(KS-2PS) are studied for their K ionic conductivities by using electrochemical impedance spectroscopy (EIS). The composition 0.3KS-0.6PS-0.1KOTf is found to have the highest conductivity among the studied glassy electrolytes at ambient temperature with the value of 1.06 × 10 S cm, which is the highest of all pure K-ion-conducting glasses reported to date. Since the glass transition temperatures of the glasses are near 100 °C, as demonstrated by DSC, temperature-dependent conductivities are studied within the range of 25 to 100 °C to determine the activation energies. A Raman spectroscopic study shows the variation in the structural units PS43-, P2S74-, and P2S64- of the network former for different glassy electrolytes. It seems that there is a role of P2S74- and P2S64- in K-ion conductivity in the glassy electrolytes because the spectroscopic results are compatible with the composition-dependent, room-temperature conductivity trend.
Topics: Electrolytes; Ions; Phosphates; Potassium; Sodium Chloride; Sodium Chloride, Dietary
PubMed: 38069182
DOI: 10.3390/ijms242316855