Shift In Gating Research Articles

Regulation of Kv1.2 redox-sensitive gating by the transmembrane lectin LMAN2.

Kv1.2 potassium channels influence excitability and action potential propagation in the nervous system. Unlike closely-related Kv1 channels, Kv1.2 exhibits highly variable voltage-dependence of gating, attributed to regulation by unidentified extrinsic factors. Variability of Kv1.2 gating is strongly influenced by the extracellular redox potential, and we demonstrate that Kv1.2 currents in dorsal root ganglion sensory neurons exhibit similar variability and redox sensitivity as observed when the channel is heterologously expressed in cell lines. We used a functional screening approach to test the effects of candidate regulatory proteins on Kv1.2 gating, using patch clamp electrophysiology. Among 52 candidate genes tested, we observed that co-expression with the transmembrane lectin LMAN2 led to a pronounced gating shift of Kv1.2 activation to depolarized voltages in CHO and L(tk-) cell lines, accompanied by deceleration of activation kinetics. Overexpression of LMAN2 promoted a slow gating mode of Kv1.2 that mimics the functional outcomes of extracellular reducing conditions, and enhanced sensitivity to extracellular reducing agents. In contrast, shRNA-mediated knockdown of endogenous LMAN2 in cell lines reduced Kv1.2 redox sensitivity and gating variability. Kv1.2 sensitivity to LMAN2 is abolished by mutation of neighboring residues F251 and T252 in the intracellular S2-S3 linker, and these also abolish redox-dependent gating changes, suggesting that LMAN2 influences the same pathway as redox for Kv1.2 modulation. In conclusion, we identified LMAN2 as a candidate regulatory protein that influences redox-dependent modulation of Kv1.2, and clarified the structural elements of the channel that are required for sensitivity.

Growth of high quality polycrystalline InGaO thin films by spray pyrolysis for coplanar thin-film transistors on polyimide substrate

The current mobile devices are moving towards flexible electronics. Introducing crystalline oxide semiconductors on flexible substrates is important to satisfy the requirements of high-resolution displays on flexible substrates. This study investigates the low-cost, as-grown polycrystalline (Poly) InGaO thin film transistor by spray pyrolysis on polyimide (PI) substrate. Grazing Incidence X-ray Diffraction (GI-XRD) measurements demonstrate that In0.8Ga0.2O, In0.7Ga0.3O, and In0.5Ga0.5O compositions exhibit crystallization on-set temperatures of ∼330, ∼350, and ∼415°C, respectively. Poly-In0.7Ga0.3O thin film with lower oxygen-vacancy (∼15 %) and less than 5 % O-H group could be achieved at the substrate temperature of 370°C. The hysteresis-free device performance with an average saturation mobility of 43.73 cm2V−1s−1 has been obtained using the poly-In0.7Ga0.3O with optimized N2O plasma treatment on the poly-oxide thin film. The TFTs show remarkable stability under humid environments and various stress conditions such as positive bias temperature, negative bias temperature, and mechanical stresses. In addition, the 96-stage gate shift register made of poly-In0.7Ga0.3O TFTs by spray pyrolysis exhibits the rising and falling times of less than 820 ns. Therefore, the poly-In0.7Ga0.3O TFTs by spray pyrolysis could be used for high-resolution, cost-effective, flexible active-matrix light-emitting displays.

An Optimized Device Structure with a Highly Stable Process Using Ferroelectric Memory in 3D NAND Flash Memory Applications

In this paper, we propose an optimized device structure with a highly stable process that addresses threshold voltage shift issues in the String-Select-Line (SSL) and Ground-Select-Line (GSL) gates using ferroelectric memory in 3D NAND flash memory applications. The proposed device utilizes nickel (Ni) instead of tungsten (W) for the GSL and SSL gates, enabling optimized polarization properties during the annealing process and leveraging the disparity in thermal expansion coefficients. Notably, the difference in thermal expansion coefficient from tungsten (W), employed in other Word Line (WL) gates, allows effective control over polarization properties. To validate the proposed structure, we fabricated and measured a Metal–Ferroelectric–Insulator–Silicon (MFIS) capacitor utilizing Hafnium–Zirconium Oxide (HZO) material. The measurement results indicate that a change in the upper metal layer results in a more than fivefold increase in the variance of polarization characteristics between the WL gates (responsible for the memory function) and the SSL and GSL gates dedicated to channel control. In addition, process simulation was conducted using the same device structure, confirming the application of tensile stress to the HZO thin film in the case of a W electrode and compressive stress in the case of a Ni electrode. Furthermore, applying this controlled polarization characteristic parameter to the 3D NAND flash memory structure revealed a reduction in the threshold voltage shift of the control gate from a previous change of 2.6 V or more to 0.05 V, facilitating stable control.

Dynamics of one two-level-atom interacting with a multiple cavity modes

We discuss how to implement quantum logic gates by considering a two-level-atom driven by a strong microwave field and successively interacting with m+1 cavity modes. The scheme is insensitive to the initial state of the atom, and the operation time is independent of the number of cavity modes involved in the system operations. This scheme is used to realize two quantum logic gates (m-target-qubit controlled-global-phase gate and Multi-qubit phase shift gate) in a time much shorter than the photonic lifetime. We also studied the influence of decoherence on the fidelity. In general, our system is reasonably less sensitive to the photonic and atomic decay rates and therefore it can be experimentally realized.

High Performance Amorphous In0.5Ga0.5O Thin‐Film Transistor Embedded with Nanocrystalline In2O3 Dots for Flexible Display Application

AbstractHigh‐performance, coplanar amorphous In0.5Ga0.5O (a‐IGO) thin film transistor (TFT) on a polyimide (PI) substrate deposited by spray pyrolysis (SP) is reported. The SP a‐IGO film deposited at 370 °C has less than 8% nanocrystalline‐In2O3 dots and a mass density of 6.6 g cm−3. The a‐IGO TFT on PI exhibits linear mobility over 30 cm2 V−1 s−1 and a negligible shift in threshold voltage (ΔVTH = <0.3 V) under positive bias (+20 V) at 60 °C for 1 h. The TFT performance is stable even when bent to a radius of ≈1 mm. The X‐ray photoelectron spectroscopy results of the SP a‐IGO deposited at 370 °C indicate the O‐vacancy (Vo) related defects of 25.79% and hydroxyl (OH) at less than 3%, indicating a good active/gate insulator interface. A seven‐stage ring oscillator made of SP a‐IGO TFTs exhibits a high oscillation frequency (>2.3 MHz) with a low propagation delay time of ≈30 ns per stage at a supply voltage (VDD) of 15 V. The fabricated gate shift register circuit works up to the last stage without any decrement of the input voltage (15 V) with rising and falling times less than 0.8 µs. Therefore, the coplanar a‐IGO TFT by SP deposited at 370 °C is a promising candidate for low‐cost, flexible TFT backplanes of foldable electronics.

A novel KCNC1 gain-of-function variant causing developmental and epileptic encephalopathy: "Precision medicine" approach with fluoxetine.

Variable phenotypes, including developmental encephalopathy with (DEE) or without seizures and myoclonic epilepsy and ataxia due to potassium channel mutation, are caused by pathogenetic variants in KCNC1, encoding for Kv3.1 channel subunits. In vitro, channels carrying most KCNC1 pathogenic variants display loss-of-function features. Here, we describe a child affected by DEE with fever-triggered seizures, caused by a novel de novo heterozygous missense KCNC1 variant (c.1273G>A; V425M). Patch-clamp recordings in transiently transfected CHO cells revealed that, compared to wild-type, Kv3.1 V425M currents (1) were larger, with membrane potentials between -40 and +40 mV; (2) displayed a hyperpolarizing shift in activation gating; (3) failed to inactivate; and (4) had slower activation and deactivation kinetics, consistent with a mixed functional pattern with prevalent gain-of-function effects. Exposure to the antidepressant drug fluoxetine inhibited currents expressed by both wild-type and mutant Kv3.1 channels. Treatment of the proband with fluoxetine led to a rapid and prolonged clinical amelioration, with the disappearance of seizures and an improvement in balance, gross motor skills, and oculomotor coordination. These results suggest that drug repurposing based on the specific genetic defect may provide an effective personalized treatment for KCNC1-related DEEs.

Twist-angle dependent proximity induced spin-orbit coupling in graphene/topological insulator heterostructures

The proximity-induced spin-orbit coupling (SOC) in heterostructures of twisted graphene and topological insulators (TIs) Bi$_2$Se$_3$ and Bi$_2$Te$_3$ is investigated from first principles. To build commensurate supercells, we strain graphene and correct thus resulting band offsets by applying a transverse electric field. We then fit the low-energy electronic spectrum to an effective Hamiltonian that comprises orbital and spin-orbit terms. For twist angles 0$^\circ\leq\Theta \lessapprox 20^\circ$, we find the dominant spin-orbit couplings to be of the valley-Zeeman and Rashba types, both a few meV strong. We also observe a sign change in the induced valley-Zeeman SOC at $\Theta\approx 10^\circ$. Additionally, the in-plane spin structure resulting from the Rashba SOC acquires a non-zero radial component, except at $0^\circ$ or $30^\circ$. At $30^\circ$ the graphene Dirac cone interacts directly with the TI surface state. We therefore explore this twist angle in more detail, studying the effects of gating, TI thicknesses, and lateral shifts on the SOC parameters. We find, in agreement with previous results, the emergence of the proximitized Kane-Mele SOC, with a change in sign possible by electrically tuning the Dirac cone within the TI bulk band gap.

Transient and Sustained Ganglion Cell Light Responses Are Differentially Modulated by Intrinsically Produced Reactive Oxygen Species Acting upon Specific Voltage-Gated Na+ Channel Isoforms.

Increasing spike rates drive greater neuronal energy demand. In turn, mitochondrial ATP production leads to the generation of reactive oxygen species (ROS) that can modulate ion channel gating. Does ROS production autoregulate the excitability of a neuron? We investigated the links between retinal ganglion cell (RGC) excitability and spike activity-driven ROS production in male and female mice. Changes to the light-evoked and current-evoked spike patterns of functionally identified αRGC subtypes, along with their NaV channel-gating properties, were recorded during experimentally induced decreases and increases of intracellular ROS. During periods of highest spike rates (e.g., following light onset in ON sustained RGCs and light offset in OFF sustained RGCs), these αRGC subtypes responded to reductions of ROS (induced by catalase or glutathione monoethyl ester) with higher spike rates. Increases in ROS (induced by mercaptosuccinate, antimycin-A, or H2O2) lowered spike rates. In ON and OFF transient RGCs, there were no changes in spike rate during ROS decreases but increased ROS increased spiking. This suggests that endogenous ROS are intrinsic neuromodulators in RGCs having high metabolic demands but not in RGCs with lower energy needs. We identified ROS-induced shifts in the voltage-dependent gating of specific isoforms of NaV channels that account for the modulation of ON and OFF sustained RGC spike frequency by ROS-mediated feedback. ROS-induced changes to NaV channel gating, affecting activation and inactivation kinetics, are consistent with the differing spike pattern alterations observed in RGC subtypes. Cell-autonomous generation of ROS during spiking contributes to tuning the spike patterns of RGCs.SIGNIFICANCE STATEMENT Energy production within retinal ganglion cells (RGCs) is accompanied by metabolic by-products harmful to cellular function. How these by-products modulate the excitability of RGCs bears heavily on visual function and the etiology of optic neuropathies. A novel hypothesis of how RGC metabolism can produce automodulation of electrical signaling was tested by identifying the characteristics and biophysical origins of changes to the excitability of RGCs caused by oxidizing by-products in the retina. This impacts our understanding of the pathophysiology of RGC dysfunction, supporting an emerging model in which increases in oxidizing chemical species during energy production, but not necessarily bioenergetic failure, lead to preferential degeneration of specific subtypes of RGCs, yielding loss of different aspects of visual capacity.

Spliced isoforms of the cardiac Nav1.5 channel modify channel activation by distinct structural mechanisms.

Alternative splicing is an important cellular mechanism that fine tunes the gating properties of both voltage- and ligand-gated ion-channels. The cardiac voltage-gated sodium channel, Nav1.5, is subject to alternative splicing of the DI S3-S4 linker, which generates two types of channels with different activation properties. Here, we show that the gating differences between the adult (mH1) and neonatal (Nav1.5e) isoforms of Nav1.5 are mediated by two amino acid residues: Thr/Ser at position 207 and Asp/Lys at position 211. Electrophysiological experiments, in conjunction with molecular dynamics simulations, revealed that each residue contributes equally to the overall gating shifts in activation, but that the underlying structural mechanisms are different. Asp/Lys at position 211 acts through electrostatic interactions, whereas Thr/Ser at position 207 is predicted to alter the hydrogen bond network at the top of the S3 helix. These distinct structural mechanisms work together to modify movement of the voltage-sensitive S4 helix to bring about channel activation. Interestingly, mutation of the homologous Asp and Thr residues of the skeletal muscle isoform, Nav1.4, to Lys and Ser, respectively, confers a similar gating shift in channel activation, suggesting that these residues may fulfill a conserved role across other Nav channel family members.

Role of gate electrode in influencing interface trap sensitivity in SOI tunnel FETs

This article reports the response of a silicon-on-insulator tunnel field-effect transistor (TFET) to the presence of semiconductor/ gate dielectric interface traps. A systematic strategy is designed keeping in view different parameters which are related to the gate of the device. Acceptor-like traps, and donor-like traps with Gaussian distribution are considered at the said interface for the entire analysis. Sensitivity % is taken as a figure of merit which measures the deviation of the drain current in presence of traps from the cases with no traps. The effect of temperature on interface traps, and the effect of interface traps on gate leakage current are analyzed. The acceptor-like traps are found to affect the on-state regime, and the donor-like traps are found to affect the ambipolar regime. Analyses on gate–drain underlap, gate–source overlap, shift of entire gate over the device, and gate work-function suggest that the gate electrode plays an important role in determining the sensitivity of the TFETs. Furthermore, noise spectral densities in presence of flicker, diffusion, and monopolar generation-recombination noise sources, and interface traps are reported.

HCN Channel Phosphorylation Sites Mapped by Mass Spectrometry in Human Epilepsy Patients and in an Animal Model of Temporal Lobe Epilepsy

Because hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels modulate the excitability of cortical and hippocampal principal neurons, these channels play a key role in the hyperexcitability that occurs during the development of epilepsy after a brain insult, or epileptogenesis. In epileptic rats generated by pilocarpine-induced status epilepticus, HCN channel activity is downregulated by two main mechanisms: a hyperpolarizing shift in gating and a decrease in amplitude of the current mediated by HCN channels, Ih. Because these mechanisms are modulated by various phosphorylation signaling pathways, we hypothesized that phosphorylation changes occur at individual HCN channel amino acid residues (phosphosites) during epileptogenesis. We collected CA1 hippocampal tissue from male Sprague Dawley rats made epileptic by pilocarpine-induced status epilepticus, and age-matched naïve controls. We also included resected human brain tissue containing epileptogenic zones (EZs) where seizures arise for comparison to our chronically epileptic rats. After enrichment for HCN1 and HCN2 isoforms by immunoprecipitation and trypsin in-gel digestion, the samples were analyzed by mass spectrometry. We identified numerous phosphosites from HCN1 and HCN2 channels, representing a novel survey of phosphorylation sites within HCN channels. We found high levels of HCN channel phosphosite homology between humans and rats. We also identified a novel HCN1 channel phosphosite S791, which underwent significantly increased phosphorylation during the chronic epilepsy stage. Heterologous expression of a phosphomimetic mutant, S791D, replicated a hyperpolarizing shift in Ih gating seen in neurons from chronically epileptic rats. These results show that HCN1 channel phosphorylation is altered in epilepsy and may be of pathogenic importance.

Mechanism of pore opening in the calcium-activated chloride channel TMEM16A

The anion channel TMEM16A is activated by intracellular Ca2+ in a highly cooperative process. By combining electrophysiology and autocorrelation analysis, we investigated the mechanism of channel activation and the concurrent rearrangement of the gate in the narrow part of the pore. Features in the fluctuation characteristics of steady-state current indicate the sampling of intermediate conformations that are successively occupied during gating. The initial step is related to conformational changes induced by Ca2+ binding, which is ensued by rearrangements that open the pore. Mutations in the gate shift the equilibrium of transitions in a manner consistent with a progressive destabilization of this region during pore opening. We come up with a mechanism of channel activation where the binding of Ca2+ induces conformational changes in the protein that, in a sequential manner, propagate from the binding site and couple to the gate in the narrow pore to allow ion permeation.

Intrinsic plasticity of cerebellar stellate cells is mediated by NMDA receptor regulation of voltage-gated Na+ channels.

We show that NMDA receptors (NMDARs) elicit a long-term increase in the firing rates of inhibitory stellate cells of the cerebellum NMDARs induce intrinsic plasticity through a Ca2+ - and CaMKII-dependent pathway that drives shifts in the activation and inactivation properties of voltage-gated Na+ (Nav ) channels An identical Ca2+ - and CaMKII-dependent signalling pathway is triggered during whole-cell recording which lowers the action potential threshold by causing a hyperpolarizing shift in the gating properties of Nav channels. Our findings open the more general possibility that NMDAR-mediated intrinsic plasticity found in other cerebellar neurons may involve similar shifts in Nav channel gating. Memory storage in the mammalian brain is mediated not only by long-lasting changes in the efficacy of neurotransmitter receptors but also by long-term modifications to the activity of voltage-gated ion channels. Activity-dependent plasticity of voltage-gated ion channels, or intrinsic plasticity, is found throughout the brain in virtually all neuronal types, including principal cells and interneurons. Although intrinsic plasticity has been identified in neurons of the cerebellum, it has yet to be studied in inhibitory cerebellar stellate cells of the molecular layer which regulate activity outflow from the cerebellar cortex by feedforward inhibition onto Purkinje cells. The study of intrinsic plasticity in stellate cells has been particularly challenging as membrane patch breakthrough in electrophysiology experiments unintentionally triggers changes in spontaneous firing rates. Using cell-attached patch recordings to avoid disruption, we show that activation of extrasynaptic N-methyl-d-aspartate receptors (NMDARs) elicits a long-term increase in the firing properties of stellate cells by stimulating a rise in cytosolic Ca2+ and activation of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). An identical signalling pathway is triggered during whole-cell recording which lowers the action potential threshold by causing a hyperpolarizing shift in the gating properties of voltage-gated sodium (Nav ) channels. Together, our findings identify an unappreciated role of Nav channel-dependent intrinsic plasticity in cerebellar stellate cells which, in concert with non-canonical NMDAR signalling, provides the cerebellum with an unconventional mechanism to fine-tune motor behaviour.

Is multileaf collimator tracking or gating a better intrafraction motion adaptation strategy? An analysis of the TROG 15.01 stereotactic prostate ablative radiotherapy with KIM (SPARK) trial

PurposeStereotactic Ablative Radiotherapy (SABR) has recently emerged as a favourable treatment option for prostate cancer patients. With higher doses delivered over fewer fractions, motion adaptation is a requirement for accurate delivery of SABR. This study compared the efficacy of multileaf collimator (MLC) tracking vs. gating as a real-time motion adaptation strategy for prostate SABR patients enrolled in a clinical trial. MethodsForty-four prostate cancer patients treated over five fractions in the TROG 15.01 SPARK trial were analysed in this study. Forty-nine fractions were treated using MLC tracking and 166 fractions were treated using beam gating and couch shifts. A time-resolved motion-encoded dose reconstruction method was used to evaluate the dose delivered using each motion adaptation strategy and compared to an estimation of what would have been delivered with no motion adaptation strategy implemented. ResultsMLC tracking and gating both delivered doses closer to the plan compared to when no motion adaptation strategy was used. Differences between MLC tracking and gating were small with differences in the mean discrepancy from the plan of −0.3% (CTV D98%), 1.4% (CTV D2%), 0.4% (PTV D95%), 0.2% (rectum V30Gy) and 0.0% (bladder V30Gy). On average, 0.5 couch shifts were required per gated fractions with a mean interruption duration of 1.8 ± 2.6 min per fraction treated using gating. ConclusionBoth MLC tracking and gating were effective strategies at improving the accuracy of the dose delivered to the target and organs at risk. While dosimetric performance was comparable, gating resulted in interruptions to treatment.Clinical trial registration number: NCT02397317.

Impact of Left Side Back Gate Misalignment Effect in an Analytical Tunneling Current Modeling of an Ultrathin Asymmetric DG TFET

This paper exhibits a detailed explanation of an analytical band to band tunneling current model with gate misalignment effect for an ultrathin n type Asymmetric DG TFET considering fringing effect on the non gate overlapping channel region formed due to left side shifting of back gate. Model includes leakage current around the channel-drain interface, has a great impact in sub-threshold region and verified under front gate voltage with gate length scaled to 20 nm for different back gate shifts and various back gate voltages with Silicon Dioxide (SiO2) as gate insulator. It also exhibits a good concurrence with the device simulator in representing drain voltage dependent tunneling current characteristics with different front gate voltages. We authenticate our model throughout several simulations comparing device simulator ISE TCAD results and exhibits an excellent correlation.

Gate structure dependent normally-off AlGaN/GaN heterostructure field-effect transistors with p-GaN cap layer

In this study, the influences of a p-GaN gate structure on normally-off AlGaN/GaN heterostructure field-effect transistors were evaluated. It is demonstrated that a metal-insulator-semiconductor (MIS) gate structure can effectively suppress the gate leakage current and shift the threshold voltage positively, as compared with the Schottky and ohmic gate structures. To further improve the device performance, a novel gate-first MIS gate structure was proposed by combining the self-alignment gate and low-temperature ohmic. Good ohmic contact with a contact resistance of 1.45 Ω mm was achieved after annealing at 500 °C. For the self-aligned gate structure, a threshold voltage of 2.5 V, gate swing of 16 V, and drain current density of 50 mA mm−1 were observed. Besides, the gate leakage current was reduced to a very low level in both positive and negative bias regions.

Two photon conditional phase gate based on Rydberg slow light polaritons

We analyze the fidelity of a deterministic quantum phase gate (QPG) for two photons counterpropagating as polaritons through a cloud of Rydberg atoms under the condition of electromagnetically induced transparency (EIT). We provide analytical results for the phase shift of the quantum gate, and provide an estimation for all processes leading to a reduction to the gate fidelity. Especially, the influence of losses from the intermediate level, dispersion of the photon wave packet, scattering into additional polariton channels, finite lifetime of the Rydberg state, as well as effects of transverse size of the wave packets are accounted for. We show that the flatness of the effective interaction, caused by the blockade phenomena, suppresses the corrections due to the finite transversal size. This is a strength of Rydberg-EIT setup compared to other approaches. Finally, we provide the experimental requirements for the realization of a high fidelity QPG using Rydberg polaritons.

62‐2: Highly Reliable Shift Register with Coplanar a‐IGZO TFTs by Splitting Top Gate into Dual Gates

We report the effect of gate splitting on the performance and stability of coplanar amorphous‐Indium‐Gallium‐Zinc‐Oxide (a‐IGZO) TFTs. Splitting gate reduces the threshold voltage (Vth) shift by PBTS (positive bias temperature stress) and improves the performance uniformity. The gate driver made of split gates also shows better performance and stability compared with the conventional single gate shift register

Reduced hybrid/complex N-glycosylation disrupts cardiac electrical signaling and calcium handling in a model of dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is the third most common cause of heart failure, with ~70% of DCM cases considered idiopathic. We showed recently, through genetic ablation of the MGAT1 gene, which encodes an essential glycosyltransferase (GlcNAcT1), that prevention of cardiomyocyte hybrid/complex N-glycosylation was sufficient to cause DCM that led to heart failure and early death. Our findings are consistent with increasing evidence suggesting a link between aberrant glycosylation and heart diseases of acquired and congenital etiologies. However, the mechanisms by which changes in glycosylation contribute to disease onset and progression remain largely unknown. Activity and gating of voltage-gated Na+ and K+ channels (Nav and Kv respectively) play pivotal roles in the initiation, shaping and conduction of cardiomyocyte action potentials (APs) and aberrant channel activity was shown to contribute to cardiac disease. We and others showed that glycosylation can impact Nav and Kv function; therefore, here, we investigated the effects of reduced cardiomyocyte hybrid/complex N-glycosylation on channel activity to investigate whether chronic aberrant channel function can contribute to DCM. Ventricular cardiomyocytes from MGAT1 deficient (MGAT1KO) mice display prolonged APs and pacing-induced aberrant early re-activation that can be attributed to, at least in part, a significant reduction in Kv expression and activity that worsens over time suggesting heart disease-related remodeling. MGAT1KO Nav demonstrate no change in expression or maximal conductance but show depolarizing shifts in voltage-dependent gating. Together, the changes in MGAT1KO Nav and Kv function likely contribute to observed anomalous electrocardiograms and Ca2+ handling. These findings provide insight into mechanisms by which altered glycosylation contributes to DCM through changes in Nav and Kv activity that impact conduction, Ca2+ handling and contraction. The MGAT1KO can also serve as a useful model to study the effects of aberrant electrical signaling on cardiac function and the remodeling events that can occur with heart disease progression.

Cerebellar Stellate Cell Excitability Is Coordinated by Shifts in the Gating Behavior of Voltage-Gated Na+and A-Type K+Channels

Neuronal excitability in the vertebrate brain is governed by the coordinated activity of both ligand- and voltage-gated ion channels. In the cerebellum, spontaneous action potential (AP) firing of inhibitory stellate cells (SCs) is variable, typically operating within the 5- to 30-Hz frequency range. AP frequency is shaped by the activity of somatodendritic A-type K+ channels and the inhibitory effect of GABAergic transmission. An added complication, however, is that whole-cell recording from SCs induces a time-dependent and sustained increase in membrane excitability making it difficult to define the full range of firing rates. Here, we show that whole-cell recording in cerebellar SCs of both male and female mice augments firing rates by reducing the membrane potential at which APs are initiated. AP threshold is lowered due to a hyperpolarizing shift in the gating behavior of voltage-gated Na+ channels. Whole-cell recording also elicits a hyperpolarizing shift in the gating behavior of A-type K+ channels which contributes to increased firing rates. Hodgkin–Huxley modeling and pharmacological experiments reveal that gating shifts in A-type K+ channel activity do not impact AP threshold, but rather promote channel inactivation which removes restraint on the upper limit of firing rates. Taken together, our work reveals an unappreciated impact of voltage-gated Na+ channels that work in coordination with A-type K+ channels to regulate the firing frequency of cerebellar SCs.