Ion Gating Research Articles

Gating Current Models Computed with Consistent Interactions

Gating currents of the voltage sensor involve back-and forth movements of positively charged arginines through the hydrophobic plug of the gating pore. Transient movements of the permanent charge of the arginines induce structural changes and polarization charge nearby. The moving permanent charge induces current flow everywhere. Everything interacts with everything else in this structural model so everything must interact with everything else in the mathematics, as everything does in the structure. Energy variational methods EnVarA are used to compute gating currents in which all movements of charge and mass satisfy conservation laws of current and mass. Conservation laws are partial differential equations in space and time. Ordinary differential equations cannot capture such interactions with one set of parameters. Indeed, they may inadvertently violate conservation of current. Conservation of current is particularly important since small violations (<0.01%) quickly (microseconds) produce forces that destroy molecules. Our model reproduces signature properties of gating current: (1) equality of ON and OFF charge (2) saturating voltage dependence and (3) many (but not all) details of the shape of charge movement as a function of voltage, time, and solution composition. The model computes gating current flowing in the baths produced by arginines moving in the voltage sensor. The movement of arginines induces current flow everywhere producing ‘capacitive’ pile ups at the ends of the channel. Such pile-ups at charged interfaces are well studied in measurements and theories of physical chemistry but they are not typically included in models of gating current or ion channels. The pile-ups of charge change local electric fields, and they store charge in series with the charge storage of the arginines of the voltage sensor. Implications are being investigated.

Ion mobility mass spectrometry of peptide, protein, and protein complex ions using a radio-frequency confining drift cell.

Ion mobility mass spectrometry experiments enable the characterization of mass, assembly, and shape of biological molecules and assemblies. Here, a new radio-frequency confining drift cell is characterized and used to measure the mobilities of peptide, protein, and protein complex ions. The new drift cell replaced the traveling-wave ion mobility cell in a Waters Synapt G2 HDMS. Methods for operating the drift cell and determining collision cross section values using this experimental set up are presented within the context of the original instrument control software. Collision cross sections for 349 cations and anions are reported, 155 of which are for ions that have not been characterized previously using ion mobility. The values for the remaining ions are similar to those determined using a previous radio-frequency confining drift cell and drift tubes without radial confinement. Using this device under 2 Torr of helium gas and an optimized drift voltage, denatured and native-like ions exhibited average apparent resolving powers of 14.2 and 16.5, respectively. For ions with high mobility, which are also low in mass, the apparent resolving power is limited by contributions from ion gating. In contrast, the arrival-time distributions of low-mobility, native-like ions are not well explained using only contributions from ion gating and diffusion. For those species, the widths of arrival-time distributions are most consistent with the presence of multiple structures in the gas phase.

PH and Calcium Cooperative Regulation Nanofluidic Gating Device

In living body, Ca 2 + -responsive ion channels play crucial roles in many biological activities. Inspired by nature, the design and fabrication of artificial smart nanochannels system become a very significant research subject, mimicking the biological Ca 2 + -responsive signals in ion channels. In this article, by using track-etched artificial polyethylene terephthalate (PET) multiporous membrane materials and modifying intelligent molecules O-Phospho-L-tyrosine (OPLT) through chemical modification method, we demonstrate a new biomimetic artificial smart responsive ion channel system, which presents the cooperative response to pH and calcium. The nanosystem shows ion selective transport, ion gating and ion rectification prop- erty, which is similar to the property of biological Ca 2 + -responsive ion channels. And the cooperative responsive property of pH and calcium in OPLT modified nanochannels was also investigated by measuring the current-voltage (I-V) curves. At a low pH value, the surface charge of the nanochannels walls is positive as a result of the amino group ( 3 NH +

生体システムから発想した機能膜：膜材料の階層構造と機能発現

Systematic membrane design is important to develop next generation synthetic–membranes, and necessary functions are not only separation but also molecular recognitions and actuation like bio–membranes. Those functions should be coordinated in the membrane pores and the assembly to maximize a specific output. We should systematically design the multi functions in the membranes. A novel molecular recognition gating membrane was developed. The device facilitates to make a new process showing bio–membrane–like systematic functions. The membrane is a porous thin film, and the pores rapidly open and close in response to specific ion or molecular signals. The molecular recognition ion gating membranes can control membrane flux, molecular weight cut–off curve, and osmotic pressure. Those functions can be coordinated and make an oscillation device which the membrane pores can be opened and closed autonomously with time. Those membranes can be applied to tissue engineering and bio–sensors. We can systematically design the multi functions from molecular level to macro level in the pores, and the hierarchical design and developing approach was explained.

The hitchhiker’s guide to the voltage-gated sodium channel galaxy

Eukaryotic voltage-gated sodium (Nav) channels contribute to the rising phase of action potentials and served as an early muse for biophysicists laying the foundation for our current understanding of electrical signaling. Given their central role in electrical excitability, it is not surprising that (a) inherited mutations in genes encoding for Nav channels and their accessory subunits have been linked to excitability disorders in brain, muscle, and heart; and (b) Nav channels are targeted by various drugs and naturally occurring toxins. Although the overall architecture and behavior of these channels are likely to be similar to the more well-studied voltage-gated potassium channels, eukaryotic Nav channels lack structural and functional symmetry, a notable difference that has implications for gating and selectivity. Activation of voltage-sensing modules of the first three domains in Nav channels is sufficient to open the channel pore, whereas movement of the domain IV voltage sensor is correlated with inactivation. Also, structure–function studies of eukaryotic Nav channels show that a set of amino acids in the selectivity filter, referred to as DEKA locus, is essential for Na+ selectivity. Structures of prokaryotic Nav channels have also shed new light on mechanisms of drug block. These structures exhibit lateral fenestrations that are large enough to allow drugs or lipophilic molecules to gain access into the inner vestibule, suggesting that this might be the passage for drug entry into a closed channel. In this Review, we will synthesize our current understanding of Nav channel gating mechanisms, ion selectivity and permeation, and modulation by therapeutics and toxins in light of the new structures of the prokaryotic Nav channels that, for the time being, serve as structural models of their eukaryotic counterparts.

Smart modification of the single conical nanochannel to fabricate dual-responsive ion gate by self-initiated photografting and photopolymerization

A simple, rapid and general method of self-initiated photografting and photopolymerization (SIPGP) was first introduced to fabricate dual-responsive nanochannel with a solid-state conical nanopore for the first time. The high density of carboxyl and hydroxyl groups on the internal surface of the etched poly(ethylene terephthalate) (PET) nanochannel acted as photo-active sites to provide further growth and amplification of polymer brushes via SIPGP. Poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) was chosen as a prototypical polymer which can be grafted on the surface of the nanochannel with high efficiency. SIPGP provided a smart and simple strategy to graft polymer brush on the surface of the nanochannel without the need of a surface bonded initiator. Series of characterizations including current–voltage curves, scanning electron microscope (SEM), X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM) indicated the successful construction of the polymer. The functionalized nanochannel was finally used for the construction of smart gate with perfect responsibility, reversibility and stability towards CO2 and temperature. This modification strategy combined with unique character of the polymer may hold a great potential in building various smart responsive systems.

Physical basis of apparent pore dilation of ATP-activated P2X receptor channels.

The selectivity of ion channels is fundamental for their roles in electrical and chemical signaling and in ion homeostasis. Although most ion channels exhibit stable ion selectivity, the prevailing view of purinergic P2X receptor channels, transient receptor potential V1 (TRPV1) channels and acid-sensing ion channels (ASICs) is that their ion conduction pores dilate upon prolonged activation. We investigated this mechanism in P2X receptors and found that the hallmark shift in equilibrium potential observed with prolonged channel activation does not result from pore dilation, but from time-dependent alterations in the concentration of intracellular ions. We derived a physical model to calculate ion concentration changes during patch-clamp recordings, which validated our experimental findings and provides a quantitative guideline for effectively controlling ion concentration. Our results have fundamental implications for understanding ion permeation and gating in P2X receptor channels, as well as more broadly for using patch-clamp techniques to study ion channels and neuronal excitability.

A Bioinspired Switchable and Tunable Carbonate‐Activated Nanofluidic Diode Based on a Single Nanochannel

AbstractA smart nanofluidic diode that exhibits both ion gating and ion current rectification has been developed using a 1‐(4‐amino‐phenyl)‐2,2,2‐trifluoro‐ethanone‐functionalized, conical nanochannel in a polyimide (PI) membrane. The switch‐like property can be tuned by controlling the wettability and charge distribution with carbonate ions. Such a nanodevice is advantageous for precisely controlling conductive states with an ultrahigh gating ratio of up to 5000, and a high rectification ratio of 27. By virtue of the high selectivity and sensitivity for carbonate ions, this nanofluidic diode may find applications in carbonate or carbon dioxide detection.

A Bioinspired Switchable and Tunable Carbonate-Activated Nanofluidic Diode Based on a Single Nanochannel.

A smart nanofluidic diode that exhibits both ion gating and ion current rectification has been developed using a 1-(4-amino-phenyl)-2,2,2-trifluoro-ethanone-functionalized, conical nanochannel in a polyimide (PI) membrane. The switch-like property can be tuned by controlling the wettability and charge distribution with carbonate ions. Such a nanodevice is advantageous for precisely controlling conductive states with an ultrahigh gating ratio of up to 5000, and a high rectification ratio of 27. By virtue of the high selectivity and sensitivity for carbonate ions, this nanofluidic diode may find applications in carbonate or carbon dioxide detection.

A spin filter transistor made of topological Weyl semimetal

Topological boundary states (TBSs) in Weyl semimetal (WSM) thin film can induce tunneling. Such TBSs are spin polarized inducing spin-polarized current, which can be used to build a spin-filter transistor (SFT) in spintronics. The WSM thin film can be viewed as a series of decoupled quantum anomalous Hall insulator (QAHI) wires connected in parallel, so compared with the proposed SFT made of QAHI nanowire, this SFT has a broader working energy region and easier to be manipulated. And within a narrow region outside this energy domain, the 2D WSM is with very low conductance, so it makes a good on/off switch device with controllable chemical potential induced by liquid ion gate. We also construct a loop device made of 2D WSM with inserted controllable flux to control the polarized current.

Increased sialylation as a phenomenon in accommodation of the parasitic nematode Trichinella spiralis (Owen, 1835) in skeletal muscle fibres.

The biology of sialic acids has been an object of interest in many models of acquired and inherited skeletal muscle pathology. The present study focuses on the sialylation changes in mouse skeletal muscle after invasion by the parasitic nematode Trichinella spiralis (Owen, 1835). Asynchronous infection with T. spiralis was induced in mice that were sacrificed at different time points of the muscle phase of the disease. The amounts of free sialic acid, sialylated glycoproteins and total sialyltransferase activity were quantified. Histochemistry with lectins specific for sialic acid was performed in order to localise distribution of sialylated glycoconjugates and to clarify the type of linkage of the sialic acid residues on the carbohydrate chains. Elevated intracellular accumulation of α-2,3- and α-2,6-sialylated glycoconjugates was found only within the affected sarcoplasm of muscle fibres invaded by the parasite. The levels of free and protein-bound sialic acid were increased and the total sialyltransferase activity was also elevated in the skeletal muscle tissue of animals with trichinellosis. We suggest that the biological significance of this phenomenon might be associated with securing integrity of the newly formed nurse cell within the surrounding healthy skeletal muscle tissue. The increased sialylation might inhibit the affected muscle cell contractility through decreased membrane ion gating, helping the parasite accommodation process.

Influence of humidity and air pressure on the ion mobility based on drift tube method

The measurement of ion mobility is important for calculating the corona loss of the transmission lines, and for establishing corona loss and ion current models that take humidity and air pressure into consideration. This paper describes a needle-ring corona discharge experiment setup based on a prior study, which simulates different humidity and air pressure conditions; it is observed that the execution of the ion gate is improved in this experiment from off-on-off to off-on to achieve higher ion current amplitude. Additionally, positive and negative ion mobility under different humidity and air pressure is obtained, with the positive ion mobility measurements in the range of 1.1126 to 1.9167 cm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> /V·s, and the negative ion mobility measurements in the range of 1.3574 to 2.5643 cm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> /V·s. The experimental results indicate that ion mobility decreases nonlinearly with increase in humidity, but trends towards saturation in the 30%-70% relative humidity range. Finally, a parameter correction method for calibrating the relationship among the ion mobility, humidity, and air pressure is proposed.

Molecular pathophysiology and pharmacology of the voltage-sensing module of neuronal ion channels.

Voltage-gated ion channels (VGICs) are membrane proteins that switch from a closed to open state in response to changes in membrane potential, thus enabling ion fluxes across the cell membranes. The mechanism that regulate the structural rearrangements occurring in VGICs in response to changes in membrane potential still remains one of the most challenging topic of modern biophysics. Na+, Ca2+ and K+ voltage-gated channels are structurally formed by the assembly of four similar domains, each comprising six transmembrane segments. Each domain can be divided into two main regions: the Pore Module (PM) and the Voltage-Sensing Module (VSM). The PM (helices S5 and S6 and intervening linker) is responsible for gate opening and ion selectivity; by contrast, the VSM, comprising the first four transmembrane helices (S1–S4), undergoes the first conformational changes in response to membrane voltage variations. In particular, the S4 segment of each domain, which contains several positively charged residues interspersed with hydrophobic amino acids, is located within the membrane electric field and plays an essential role in voltage sensing. In neurons, specific gating properties of each channel subtype underlie a variety of biological events, ranging from the generation and propagation of electrical impulses, to the secretion of neurotransmitters and to the regulation of gene expression. Given the important functional role played by the VSM in neuronal VGICs, it is not surprising that various VSM mutations affecting the gating process of these channels are responsible for human diseases, and that compounds acting on the VSM have emerged as important investigational tools with great therapeutic potential. In the present review we will briefly describe the most recent discoveries concerning how the VSM exerts its function, how genetically inherited diseases caused by mutations occurring in the VSM affects gating in VGICs, and how several classes of drugs and toxins selectively target the VSM.

Quantitative Decomposition of Dynamics of Mathematical Cell Models: Method and Application to Ventricular Myocyte Models.

Mathematical cell models are effective tools to understand cellular physiological functions precisely. For detailed analysis of model dynamics in order to investigate how much each component affects cellular behaviour, mathematical approaches are essential. This article presents a numerical analysis technique, which is applicable to any complicated cell model formulated as a system of ordinary differential equations, to quantitatively evaluate contributions of respective model components to the model dynamics in the intact situation. The present technique employs a novel mathematical index for decomposed dynamics with respect to each differential variable, along with a concept named instantaneous equilibrium point, which represents the trend of a model variable at some instant. This article also illustrates applications of the method to comprehensive myocardial cell models for analysing insights into the mechanisms of action potential generation and calcium transient. The analysis results exhibit quantitative contributions of individual channel gating mechanisms and ion exchanger activities to membrane repolarization and of calcium fluxes and buffers to raising and descending of the cytosolic calcium level. These analyses quantitatively explicate principle of the model, which leads to a better understanding of cellular dynamics.

Rapid Mass Analysis of Reserpine and Arginine by Ion Trap Mass Spectrometer

Abstract A fast mass analysis method using digital ion trap technology was reported. The mass analysis was realized by scanning the frequency of digital RF voltage and dipole ion resonance voltage during ion injection period without the conventional ion cooling, ion resonance ejection or ion cleaning process. It can decrease about three fourth of traditional analysis time using ion trap mass spectrometry. The ion signal was optimized through the modification of frequency scanning rate, ion gate voltage and other experimental parameters. For example, an optimal mass spectroscopy of reserpine ( m / z 609) and arginine ( m / z 174) were obtained when the ion gate voltage was 9 V and the digital RF frequency was scanned from 1 MHz to 400 kHz at rate of 2385 Th s −1 . The results indicated that the obtained mass spectra were in very good agreement with conventional analytical method using ion trap mass analyzer.

A light-regulated synthetic ion channel constructed by an azobenzene modified hydraphile

Biological ion channels are key molecules for cellular regulation and communication. To mimic the structure and functions of nature ion channels, a new class of light-regulated transmembrane ion channels was reported based on tri(macrocycle) hydraphile and azobenzene photoswitch (hydraphile 1). The liposome-based proton transport assays showed that hydraphile 1 exhibited excellent transmembrane activity (Y), and Ymax arrived 0.7 at 40 μmol/L. The successful isomerization of azobenzene moiety was confirmed and qualified by UV and NMR spectra. Upon alternative irradiation of 365 nm UV light and 450 nm visible light, the transmembrane activity of hydraphile 1 was regulated between 0.35 and 0.5, reversibly. All the obtained results have demonstrated the promise of developing excellent synthetic ion channels with ion gating properties based on simple molecular design.

Synthetic Asymmetric‐Shaped Nanodevices with Symmetric pH‐Gating Characteristics

Synthetic stimuli‐gated nanodevices displaying intelligent ion transport properties similar to those observed in biological ion channels have attracted increasing interests for their wide potential applications in biosensors, nanofluidics, and energy conversions. Here, bioinspired asymmetric shaped nanodevices are reported that can exhibit symmetric and linear pH‐gating ion transport features based on polyelectrolyte‐asymmetric‐functionalized asymmetric hourglass‐shaped nanochannels. The pH‐responsive polymer brushes grafted on the inner channel surface are acted as a gate that open and close in response to external pH changing to linearly and symmetrically regulate transmembrane ionic currents of the channel. A complete experimental characterization of the pH‐dependent ion transport behaviors of the nanodevice and a comprehensive discussion of the experimental results in terms of theoretical simulation are also presented. Both experimental and theoretical data shown in this work demonstrate the feasibility of using the asymmetric chemical modification method to achieve symmetric pH gating behaviors inside the asymmetric nanochannels, and lay the foundation to build diverse stimuli‐gated artificial asymmetric shaped ion channels with symmetric gating ion transport features.

Multiple Closed States of the Ryanodine Receptor Determined by CRYOEM

Ryanodine receptors (RyRs) are intracellular ion channels involved in Ca2+ release from internal stores in excitable cells. These channels are the largest channels known and are homotetramers, sizing ∼2,26 MDa. The 3D structure of RyR1 in it open and close states was determined previously, revealing that the ion gate opening mechanism rely on long-range conformational changes over 100 Å. The RyR gating properties are highly regulated by Ca2+, Mg2+, ATP, and FKBP12. The native conformation of RyR1 in presence of physiological concentrations of Mg2+ and ATP is unknown. Here we determine the 3D structure of RyR1 in non-activating conditions (submicromolar Ca2+) in the presence of Mg2+ and an ATP analog, but in a flexible conformation by absence of FKPBP12. This new structure was determined using cryoEM and image processing. The resulting 3D structure is in the closed conformation when compared to 3D reconstructions of RyR1 in open and closed conditions in presence of FKBP12 determined previously. In addition, from the comparison among several 3D reconstructions, we establish new conformation-function correlations. We find that the rhomboid structures formed by domains 2-4-5-6 situated far away from the ion gate move as a whole during gating, and define a “flexion angle” that appears to be correlated with the degree of opening of the channel, whereby the flexion angle after adding Mg2+ and ATP shifts by 3 degrees towards the closed state. In conclusion this research suggests that physiological concentrations of Mg2+ and ATP shift the RyR1 conformation toward the closed conformation and also suggests that the closed conformation encompasses sub-states.

Transmission of a Drift Tube Ion Mobility Spectrometer, Connected with a Mass Spectrometer

In this work it is experimentally showed that transmission of atmospheric drift tube ion mobility spectrometer (DT-IMS), connected with mass spectrometer (MS), depends on ion mobility of investigated compounds, because of depletion effect of Bradbury-Nielson ion gate (IG), which previously has been approved only by standalone DT-IMS. Theoretical estimation of depletion width of IG is in good agreement with experimental data. Also it is found, that ion lost due to its pulsing work of IG are few times smaller, than its duty cycle. It's explained by difference in influence of coulomb repulsion at 100% and 1% duty cycle – in first case it's significant versus second case, when coulomb repulsion become negligibly small, that reduces lost of ions on entrance of MS interface.

Gating Mechanisms of Store-Operated CRAC Channels

In many animal cells, stimulation of cell surface receptors coupled to G proteins or tyrosine kinases mobilizes Ca2+ influx through store-operated Ca2+ release-activated Ca2+ (CRAC) channels. The ensuing Ca2+ entry regulates a wide variety of effector cell responses including transcription, motility, and proliferation. The physiological importance of CRAC channels for human health is underscored by studies indicating that mutations in CRAC channel genes produce a spectrum of devastating diseases including chronic inflammation, muscle weakness, and a severe combined immunodeficiency syndrome. Moreover, from a basic science perspective, CRAC channels exhibit a unique biophysical fingerprint characterized by exquisite Ca2+-selectivity, store-operated gating, and distinct pore properties and therefore serve as fascinating ion channels for understanding the biophysical mechanisms of ion permeation and gating. Studies in the last decade have revealed the cellular and molecular choreography of the CRAC channel activation process, and it is now established that opening of CRAC channels is governed through direct interactions between the pore-forming Orai proteins, and the ER Ca2+ sensors, STIM1 and STIM2. Here, I will discuss recent work in our laboratory that seeks to understand the molecular rearrangements in the CRAC channel protein underlying the opening of the pore.