Voltage-dependent Gating Research Articles

Interplay between Coulomb blockade and Josephson effect in a topological superconductor–quantum dot device

We study the behavior of a topological Josephson junction in which two topological superconductors are coupled through a quantum dot. We focus on the case with the bulk superconducting gap being the largest energy scale. Two parameter regimes are investigated: a weak tunneling between the dot and the superconductors, with the dot near its charge degeneracy point, and a strong tunneling regime in which the transmission between the dot and the superconductors is nearly perfect. We show that in the former situation, the Andreev spectrum for each sector with fixed fermion parity consists of only two levels, which gives rise to the nontrivial current-phase relation. Moreover, we study the Rabi oscillation between the two levels and indicates that the corresponding frequency is a $4\pi$-periodic function of the phase difference between the two superconductors, which is immune to the quasiparticle poisoning. In the latter case, we find that the Coulomb charging energy enhances the effect of backscattering at the interfaces between the dot and the superconductors. Both the temperature and the gate-voltage dependence of the critical Josephson current are examined.

NFATc4 and myocardin synergistically up-regulate the expression of LTCC α1C in ET-1-induced cardiomyocyte hypertrophy

AimsDysregulation of Ca2+ is a central cause of cardiac hypertrophy. The α1C subunit of L-type Ca2+ channel (LTCC) is a pore-forming protein which is responsible for the voltage-dependent channel gating and channel selectivity for Ca2+. Myocardin and nuclear factor of activated T-cells c4 (NFATc4) are two key transcription factors in cardiac hypertrophy. We aimed to investigate the underlying mechanism of the transcriptional regulation of LTCC α1C by myocardin and NFATc4 in hypertrophic cardiomyocytes. Main methodsEndothelin-1 (ET-1) was used to induce cardiomyocyte hypertrophy. Cyclosporin A (CSA) was used to block the activation of calcineurin/NFATc4 pathway in ET-1-treated cardiomyocytes and the expression of LTCC α1C were examined. Overexpression or RNAi interfering experiments were performed to investigate the effects of NFATc4 or myocardin on the transcriptional regulation of LTCC α1C. Interactions between NFATc4 and myocardin or the association of NFATc4 with myocardin promoter were assessed via Co-IP or ChIP assays respectively. Key findingsIn the present study, we found that ET-1 stimulated LTCC α1C transcription in neonatal rat cardiomyocytes partially via the activation of calcineurin/NFATc4 pathway. Overexpression of NFATc4 or myocardin promoted LTCC α1C expression in cardiomyocytes. Ca2+ channel blocker verapamil or knockdown of α1C inhibited myocardin-induced cardiomyocyte hypertrophy. Further studies showed that NFATc4 interacted with myocardin to synergistically activate the expression of LTCC α1C, moreover, NFATc4 activated myocardin expression by binding to its promoter. SignificanceOur results suggest a novel mechanism of the transcriptional regulation of LTCC α1C by synergistic activities of NFATc4 and myocardin in ET-1-induced cardiomyocyte hypertrophy.

Analysis of Oxide Trap Characteristics by Random Telegraph Signals in nMOSFETs With HfO2-Based Gate Dielectrics

This letter investigates the oxide trap properties in n-channel metal-oxide–semiconductor field-effect transistors with HfO2 and Hf 1-x Zr x O2/metal gate-stacks by an analysis of random telegraph signals. According to the multiphonon emission theory, the extracted relaxation energies show gate voltage dependence in devices with HfO2-based stacks. This dependence results from the different strengths of vibrations of the nearest neighbor Hf atoms of the oxygen vacancy in the immediate vicinity of the oxide trap. Furthermore, this dependence also induces an abnormal gate voltage dependence in terms of the activation energy required for electron capture. These results are confirmed by comparisons between two HfO2-based devices (HfO2 and Hf1-xZrxO2).

Quantum Hall effect in a system with an electron reservoir

Precise measurements of the magnetic-field and gate-voltage dependences of the capacitance of a field-effect transistor with an electron system in a wide GaAs quantum well have been carried out. It has been found that the capacitance minima caused by the gaps in the Landau spectrum of the electron system become anomalously wide when two size-quantization subbands are occupied. The effect is explained by retention of the chemical potential in the gap between the Landau levels of one of the subbands owing to redistribution of electrons between the subbands under a change in the magnetic field. The calculation taking into account this redistribution has been performed in a model of the electron system formed by two two-dimensional electron layers. The calculation results describe both the wide capacitance features and the observed disappearance of certain quantum Hall effect states.

Synthesis and Characterization of Isoindigo[7,6-g]isoindigo-Based Donor–Acceptor Conjugated Polymers

Four donor (D)–acceptor (A) conjugated polymers with isoindigo[7,6-g]isoindigo ([3E,8E]-3,8-bis(2-oxoindolin-3-ylidene)-6,8-dihydroindolo[7,6-g]indole-2,7(1H,3H)-dione, DIID) as A-unit and thiophene derivatives as D-units were synthesized by Stille polycondensation. Optical and electrochemical properties of the polymers were studied by UV–vis–NIR absorption spectrometer and cyclic voltammetry. Compared with isoindigo-based analogues, the polymers display much broader absorption spectra (covering 400–950 nm) and remarkably lower bandgaps (ca. 1.3 eV). All polymers showed ambipolar transport properties as evaluated by bottom-gate/top-contact (BGTC) and top-gate/bottom-contact (TGBC) organic thin film transistors (OTFTs) in air. Gate-voltage-dependent hole mobility (μh) was observed for BGTC devices, while the mobility of TGBC devices exhibited weak gate-voltage dependence. P3 delivered the best device performance. At the optimized thermal annealing temperature (200 °C), a μh of 1.79 cm2/(V s) and an electro...

Identification of an HV1 voltage‐gated proton channel in insects

The voltage-gated proton channel 1 (HV 1) is an important component of the cellular proton extrusion machinery and is essential for charge compensation during the respiratory burst of phagocytes. HV 1 has been identified in a wide range of eukaryotes throughout the animal kingdom, with the exception of insects. Therefore, it has been proposed that insects do not possess an HV 1 channel. In the present study, we report the existence of an HV 1-type proton channel in insects. We searched insect transcriptome shotgun assembly (TSA) sequence databases and found putative HV 1 orthologues in various polyneopteran insects. To confirm that these putative HV 1 orthologues were functional channels, we studied the HV 1 channel of Nicoletia phytophila (NpHV 1), an insect of the Zygentoma order, in more detail. NpHV 1 comprises 239 amino acids and is 33% identical to the human voltage-gated proton channel 1. Patch clamp measurements in a heterologous expression system showed proton selectivity, as well as pH- and voltage-dependent gating. Interestingly, NpHV 1 shows slightly enhanced pH-dependent gating compared to the human channel. Mutations in the first transmembrane segment at position 66 (Asp66), the presumed selectivity filter, lead to a loss of proton-selective conduction, confirming the importance of this aspartate residue in voltage-gated proton channels. Nucleotide sequence data have been deposited in the GenBank database under accession number KT780722.

Resistance noise in epitaxial thin films of ferromagnetic topological insulators

We report detailed temperature and gate-voltage dependence of 1/f resistance noise in magnetically doped topological insulators (TI) Crx(Bi,Sb)2−xTe3. The noise is remarkably sensitive to the gate voltage, increasing rapidly as the chemical potential is moved towards the charge neutrality point. Unlike in identically prepared (Bi,Sb)2Te3 films, where mobility-fluctuations in the surface states is the dominant mechanism, the noise in the magnetic Crx(Bi,Sb)2−xTe3 originates from transport in the localized band tail of the bulk valence band. A strong increase in noise with decreasing temperature supports this scenario. At higher temperature (≥10 K), we observed large noise peaks at gate voltage-dependent characteristic temperature scales. In line with similar observations in other non-magnetic TI systems, we attribute these peaks to generation-recombination in the Cr-impurity band.

Editorial: Recent Advances in Voltage-Gated Sodium Channels, their Pharmacology and Related Diseases.

Editorial: Recent Advances in Voltage-Gated Sodium Channels, their Pharmacology and Related Diseases.

Schottky barrier heights at the interfaces between pure-phase InAs nanowires and metal contacts

Understanding of the Schottky barriers formed at metal contact-InAs nanowire interfaces is of great importance for the development of high-performance InAs nanowire nanoelectronic and quantum devices. Here, we report a systematical study of InAs nanowire field-effect transistors (FETs) and the Schottky barrier heights formed at the contact-nanowire interfaces. The InAs nanowires employed are grown by molecular beam epitaxy and are high material quality single crystals, and the devices are made by directly contacting the nanowires with a series of metals of different work functions. The fabricated InAs nanowire FET devices are characterized by electrical measurements at different temperatures and the Schottky barrier heights are extracted from the measured temperature and gate-voltage dependences of the channel current. We show that although the work functions of the contact metals are widely spread, the Schottky barrier heights are determined to be distributed over 35–55 meV, showing a weak but not negligible dependence on the metals. The deduced Fermi level in the InAs nanowire channels is found to be in the band gap and very close to the conduction band. The physical origin of the results is discussed in terms of Fermi level pinning by the surface states of the InAs nanowires and a shift in pinned Fermi level induced by the metal-related interface states.

An Insect Proton Channel

Voltage-gated proton channels have been identified in a wide range of eukaryotes. The channel is an important component of the cellular proton extrusion machinery and is essential for charge compensation during the respiratory burst of phagocytes. Especially in the animal kingdom voltage gated proton channels can be found consistently. However, most insect genomes analyzed so far seems to be deprived of voltage-gated proton channels. Therefore, it has been proposed that insects do not possess voltage-gated proton channels, although until recently mainly dipteran insect genomes were sequenced. Despite this long standing dogma, here we report the discovery of voltage-gated proton channels in insects. We have performed a comprehensive search in insect TSA data bases and found putative Hv homologs in basal insects and various polyneopteran species. As a prototype insect Hv channel, the proton channel of the zygentoma Nicoletia phytophila (NpHV1) is composed of 239 amino acids with protein identity of 33% to the human proton channel hHV1. Patch clamp measurements in a heterologous expression system showed proton selectivity, pH dependent and voltage dependent gating. Interestingly, NpHv1 shows a slightly enhanced pH dependent gating compared to the human channel. Mutations at position 66 (Asp66), the presumed selectivity filter, lead to a loss of proton-selective conduction, confirming the importance of the aspartate in the first transmembrane segment in all voltage-gated proton channels.

Defining the Molecular Mechanisms of Subtype Specific KCNQ2/3 Potassium Channel Activators

Epilepsy comprises a diverse set of neurological disorders that impact more than 1% of individuals worldwide. Although more than 20 drugs are available to treat epilepsy, at least 30% of patients are resistant to pharmacotherapy and have severe uncontrollable epileptic episodes. This gap in care is often attributed to the similarity in the mechanisms of action of most anti-epileptic drugs, as they only affect a subset of possible molecular targets. Retigabine is the first approved anti-epileptic drug that acts by potentiating voltage-gated potassium channels, specifically targeting KCNQ channels that underlie the neuronal M-current. Retigabine is a ‘first in class’ drug with little specificity between KCNQ2-5, and efforts are ongoing to identify drugs with better subtype specificity and fewer side effects. The retigabine analog ICA069673 (ICA73) exhibits strong selectivity for KCNQ2 over KCNQ3, but appears to have a unique mechanism, because mutations that abolish retigabine effects do not affect ICA73. Patch clamp recordings from chimeras of KCNQ2 and KCNQ3 demonstrate that ICA73 interacts with the KCNQ2 voltage sensor (S1-S4) rather than the pore region (S5-S6) targeted by retigabine. KCNQ2 point mutants throughout the KCNQ2 voltage sensor were generated based on sequence differences between KCNQ2 and KCNQ3, and screened for ICA73-sensitivity. These experiments reveal two clusters of residues that underlie separable effects of ICA73: potentiation of peak currents, and a shift in the voltage-dependence of gating. Further exploration of KCNQ channel activators will accelerate our understanding of the molecular mechanisms of their unique effects, and the determinants of subtype specific drug binding to KCNQ channels.

Molecular Locations of Gates in Potassium Channels

Understanding how ion channels open and close their pores is crucial for understanding their physiological roles. We used intracellular quaternary ammonium blockers to locate the voltage and calcium-dependent gates in MthK potassium channels from Methanobacterium thermoautotrophicum with electrophysiology, stopped-flow spectrofluorometry, and X-ray crystallography. Blockers bind in an aqueous cavity between two putative gates, an intracellular gate and the selectivity filter. Thus, these blockers directly probe gate location: an intracellular gate will prevent binding when closed, whereas a selectivity filter gate will always allow binding.A kinetic single-channel analysis of tetrabutylammonium block of MthK channels combined with X-ray crystallographic analysis of the pore with tetrabutylantimony unequivocally determined that the voltage-dependent gate, like the C-type inactivation gate in eukaryotic channels, is located at the selectivity filter. State-dependent binding kinetics suggests that MthK gating with voltage also leads to conformational changes within the cavity and intracellular pore entrance.For locating the calcium gate, we employed a Tl+ flux assay using a stopped-flow spectrofluorometer. MthK channel activity was estimated from the rate of a MthK-containing liposome-trapped fluorophore quenching due to Tl+ influx through the channels. The high-affinity blocker tetrapentylammonium, applied prior to channel activation using a sequential mixing protocol, was able to fully block closed channels, indicating that the blocker can reach its binding site in closed channels. Given that the blocker binding site is in the cytoplasmic access below the selectivity filter, these results suggest that there is also a calcium-dependent gate at the selectivity filter in MthK.

Ginsenoside Rg3 Activates Human EAG Family of K+ Channels via Allosteric Modification of Gating

The human ether-a-go-go (EAG) family of voltage-gated K+ channels, including hERG, hEAG, and hELK exhibit variable biophysical and physiological properties. Ginsenoside Rg3 (Rg3), a steroid glycoside is a potent hERG channel activator. Here we characterize the mechanisms of action of Rg3 on three EAG-family representative channels, including hERG1, hEAG1 and hELK1 heterologously expressed in Xenopus laevis oocytes. Rg3 enhanced hERG1 channel current via a negative shift in the half-point for the voltage dependence of activation (V0.5act) that saturated at −14 mV, and a profound slowing in the rate of deactivation (EC50 = 242 nM). Rg3 had no effect on the rate of activation or the voltage dependence of hERG1 inactivation gating. For hEAG1 channels, Rg3 induced a −28 mV maxiumal shift in V0.5act (EC50 = 1.18 µM) and accelerated the rate of activation (∼20-fold faster). The maximum shift in V0.5act for hELK1 channels was much greater (>-100 mV; EC50 = 176 nM). The onset of Rg3 effects upon extracellular application was very fast and rapidly reversible upon washout for all 3 channel types, indicating this large molecule (MW = 785) binds to an extracellular region. Rg3 at 3 µM had no effect on Kv1.5 channels and only affects other Kv channels at much higher concentrations. Understanding the mechanisms of action of Rg3 may facilitate the development of more potent and selective gensenosides for therapeutic use.

Identification of Glycosylation Sites Essential for Surface Expression of the CaVα2δ1 Subunit and Modulation of the Cardiac CaV1.2 Channel Activity

Alteration in the L-type current density is one aspect of the electrical remodeling observed in patients suffering from cardiac arrhythmias. Changes in channel function could result from variations in the protein biogenesis, stability, post-translational modification, and/or trafficking in any of the regulatory subunits forming cardiac L-type Ca(2+) channel complexes. CaVα2δ1 is potentially the most heavily N-glycosylated subunit in the cardiac L-type CaV1.2 channel complex. Here, we show that enzymatic removal of N-glycans produced a 50-kDa shift in the mobility of cardiac and recombinant CaVα2δ1 proteins. This change was also observed upon simultaneous mutation of the 16 Asn sites. Nonetheless, the mutation of only 6/16 sites was sufficient to significantly 1) reduce the steady-state cell surface fluorescence of CaVα2δ1 as characterized by two-color flow cytometry assays and confocal imaging; 2) decrease protein stability estimated from cycloheximide chase assays; and 3) prevent the CaVα2δ1-mediated increase in the peak current density and voltage-dependent gating of CaV1.2. Reversing the N348Q and N812Q mutations in the non-operational sextuplet Asn mutant protein partially restored CaVα2δ1 function. Single mutation N663Q and double mutations N348Q/N468Q, N348Q/N812Q, and N468Q/N812Q decreased protein stability/synthesis and nearly abolished steady-state cell surface density of CaVα2δ1 as well as the CaVα2δ1-induced up-regulation of L-type currents. These results demonstrate that Asn-663 and to a lesser extent Asn-348, Asn-468, and Asn-812 contribute to protein stability/synthesis of CaVα2δ1, and furthermore that N-glycosylation of CaVα2δ1 is essential to produce functional L-type Ca(2+) channels.

A Non-Canonical Voltage Sensor Controls Gating in K2P K+ Channels

Two-pore domain (K2P) K+ channels are major regulators of excitability that endow cells with an outwardly rectifying background ‘leak’ conductance. In some K2P channels strong voltage-dependent activation has been observed, but the mechanism remains unresolved because they lack a canonical voltage sensing domain. Here we show voltage-dependent gating is common to most K2P channels and that this voltage sensitivity originates from the movement of 3-4 ions into the high electric field of an inactive selectivity filter. Overall, this ion-flux gating mechanism generates a one-way, ‘check valve’ within the filter because outward movement of K+ induces filter opening, whereas inward movement promotes inactivation. Furthermore, many physiological stimuli switch off this flux gating mode to convert K2P channels into a leak conductance. These findings not only provide insight into the functional plasticity of a K+-selective filter, but also redefine our view of K2P channels and the mechanisms by which ion channels can sense voltage.

A Non-canonical Voltage-Sensing Mechanism Controls Gating in K2P K+ Channels

SummaryTwo-pore domain (K2P) K+ channels are major regulators of excitability that endow cells with an outwardly rectifying background “leak” conductance. In some K2P channels, strong voltage-dependent activation has been observed, but the mechanism remains unresolved because they lack a canonical voltage-sensing domain. Here, we show voltage-dependent gating is common to most K2P channels and that this voltage sensitivity originates from the movement of three to four ions into the high electric field of an inactive selectivity filter. Overall, this ion-flux gating mechanism generates a one-way “check valve” within the filter because outward movement of K+ induces filter opening, whereas inward movement promotes inactivation. Furthermore, many physiological stimuli switch off this flux gating mode to convert K2P channels into a leak conductance. These findings provide insight into the functional plasticity of a K+-selective filter and also refine our understanding of K2P channels and the mechanisms by which ion channels can sense voltage.

The episodic ataxia type 1 mutation I262T alters voltage-dependent gating and disrupts protein biosynthesis of human Kv1.1 potassium channels.

Voltage-gated potassium (Kv) channels are essential for setting neuronal membrane excitability. Mutations in human Kv1.1 channels are linked to episodic ataxia type 1 (EA1). The EA1-associated mutation I262T was identified from a patient with atypical phenotypes. Although a previous report has characterized its suppression effect, several key questions regarding the impact of the I262T mutation on Kv1.1 as well as other members of the Kv1 subfamily remain unanswered. Herein we show that the dominant-negative effect of I262T on Kv1.1 current expression is not reversed by co-expression with Kvβ1.1 or Kvβ2 subunits. Biochemical examinations indicate that I262T displays enhanced protein degradation and impedes membrane trafficking of Kv1.1 wild-type subunits. I262T appears to be the first EA1 mutation directly associated with impaired protein stability. Further functional analyses demonstrate that I262T changes the voltage-dependent activation and Kvβ1.1-mediated inactivation, uncouples inactivation from activation gating, and decelerates the kinetics of cumulative inactivation of Kv1.1 channels. I262T also exerts similar dominant effects on the gating of Kv1.2 and Kv1.4 channels. Together our data suggest that I262T confers altered channel gating and reduced functional expression of Kv1 channels, which may account for some of the phenotypes of the EA1 patient.

Understanding Sodium Channel Function and Modulation Using Atomistic Simulations of Bacterial Channel Structures.

Sodium channels are chief proteins involved in electrical signaling in the nervous system, enabling critical functions like heartbeat and brain activity. New high-resolution X-ray structures for bacterial sodium channels have created an opportunity to see how these proteins operate at the molecular level. An important challenge to overcome is establishing relationships between the structures and functions of mammalian and bacterial channels. Bacterial sodium channels are known to exhibit the main structural features of their mammalian counterparts, as well as several key functional characteristics, including selective ion conduction, voltage-dependent gating, pore-based inactivation and modulation by local anesthetic, antiarrhythmic and antiepileptic drugs. Simulations have begun to shed light on each of these features in the past few years. Despite deviations in selectivity signatures for bacterial and mammalian channels, simulations have uncovered the nature of the multiion conduction mechanism associated with Na(+) binding to a high-field strength site established by charged glutamate side chains. Simulations demonstrated a surprising level of flexibility of the protein, showing that these side chains are active participants in the permeation process. They have also uncovered changes in protein structure, leading to asymmetrical collapses of the activation gate that have been proposed to correspond to inactivated structures. These observations offer the potential to examine the mechanisms of state-dependent drug activity, focusing on pore-blocking and pore-based slow inactivation in bacterial channels, without the complexities of inactivation on multiple timescales seen in eukaryotic channels. Simulations have provided molecular views of the interactions of drugs, consistent with sites predicted in mammalian channels, as well as a wealth of other sites as potential new drug targets. In this chapter, we survey the new insights into sodium channel function that have emerged from studies of simpler bacterial channels, which provide an excellent learning platform, and promising avenues for mechanistic discovery and pharmacological development.

Effects of the β1 auxiliary subunit on modification of Rat Nav1.6 sodium channels expressed in HEK293 cells by the pyrethroid insecticides tefluthrin and deltamethrin

We expressed rat Nav1.6 sodium channels with or without the rat β1 subunit in human embryonic kidney (HEK293) cells and evaluated the effects of the pyrethroid insecticides tefluthrin and deltamethrin on whole-cell sodium currents. In assays with the Nav1.6 α subunit alone, both pyrethroids prolonged channel inactivation and deactivation and shifted the voltage dependence of channel activation and steady-state inactivation toward hyperpolarization. Maximal shifts in activation were ~18mV for tefluthrin and ~24mV for deltamethrin. These compounds also caused hyperpolarizing shifts of ~10–14mV in the voltage dependence of steady-state inactivation and increased in the fraction of sodium current that was resistant to inactivation. The effects of pyrethroids on the voltage-dependent gating greatly increased the size of sodium window currents compared to unmodified channels; modified channels exhibited increased probability of spontaneous opening at membrane potentials more negative than the normal threshold for channel activation and incomplete channel inactivation. Coexpression of Nav1.6 with the β1 subunit had no effect on the kinetic behavior of pyrethroid-modified channels but had divergent effects on the voltage-dependent gating of tefluthrin- or deltamethrin-modified channels, increasing the size of tefluthrin-induced window currents but decreasing the size of corresponding deltamethrin-induced currents. Unexpectedly, the β1 subunit did not confer sensitivity to use-dependent channel modification by either tefluthrin or deltamethrin. We conclude from these results that functional reconstitution of channels in vitro requires careful attention to the subunit composition of channel complexes to ensure that channels in vitro are faithful functional and pharmacological models of channels in neurons.

Physical model of Seebeck coefficient under surface dipole effect in organic thin-film transistors

The surface dipole effect can play an important role in the performance of charge carrier transport in organic thin-film transistors (OTFTs). In this work, we propose a physical model of Seebeck coefficient based on variable-range hopping theory in OTFTs to characterize carrier thermoelectric transport. The model effectively explains the influence of a dipole on the carrier density, energetic disorder and temperature dependence of the Seebeck effect. The gate-voltage and temperature dependence of the Seebeck effect are remarkably enhanced by a dipole, while the energetic disorder exhibits a weak dependent nature. The Seebeck coefficients calculated in this study and those obtained experimentally in a previous study were found to be in good agreement.