Intrinsic Channel Research Articles

Influence of neutron transfer channels and collective excitations in the fusion of Si28 with Zr90,92,94,96 targets

This work theoretically explores the role of neutron transfer channels and/or collective inelastic surface excitations in the fusion of $^{28}\mathrm{Si}$ with $^{90,92,94,96}\mathrm{Zr}$ targets by using the coupled channel theory and the energy dependent Woods-Saxon potential (EDWSP) model. The series of $^{90,92,94,96}\mathrm{Zr}$ targets is quite interesting due to the fact that the possibilities of neutron transfer channels with positive ground state $Q$ values increase with the increase of isotopic mass. For $^{28}\mathrm{Si}+^{90}\mathrm{Zr}$ reaction, the influences of inelastic surface excitations turned out to be important and coupling of such channels to their relative motion reproduced the experimental data. In the case of $^{28}\mathrm{Si}+^{92}\mathrm{Zr}$ reaction, in addition to consideration of low lying states such as ${2}^{+}$ and ${3}^{\ensuremath{-}}$ vibrational states of colliding nuclei, the coupling to two neutron pickup channels is necessarily required to address the sub-barrier fusion anomalies. For $^{28}\mathrm{Si}+^{94,96}\mathrm{Zr}$ reactions, the inclusions of multiphonon states of type ${2}^{+}$ and ${3}^{\ensuremath{-}}$ of colliding nuclei were not able to reproduce the fusion enhancement particularly at below barrier energies. In this case, neutron transfer channels with positive ground state $Q$ value play a crucial role in the enhancement of fusion cross-section data at sub-barrier energies and therefore must be included in the coupled channel description. In distinction, in the EDWSP model, the energy dependence in the nucleus-nucleus potential causes barrier modification effects and subsequently induces a barrier lowering phenomenon. In this way, the EDWSP based outcomes reasonably address the sub-barrier fusion anomalies of $^{28}\mathrm{Si}+^{90,92,94,96}\mathrm{Zr}$ reactions and thus impacts of dominant intrinsic channels are intrinsically included due to the dynamical nature of the energy dependent interaction potential. For studied systems, the EDWSP outcomes are able to achieve an agreement with the portion of above barrier fusion data within 10% with a probability greater than 90%. Within this model, 33 fusion data points out of 38 fusion data points lie within 5%. Only five fusion data points lie within 10% and thereby the EDWSP model adequately addresses the fusion anomalies of the chosen reactions. The smaller values of ${\ensuremath{\chi}}^{2}$ analysis for the EDWSP calculations, which range from 2.82 to 3.14, indicate that the model predictions appropriately describe the observed fusion dynamics of the studied reactions.

Graphene-based vertical thin film transistors

Vertical field effect transistors (VFETs), where the channel material is sandwiched between source-drain electrodes and the channel length is simply determined by its body thickness, have attracted considerable interest for high performance electronics owning to their intrinsic short channel length. To enable the effective gate modulation and current switching behavior, the electrode of conventional VFET is largely based on perforated metals, in which the gate electrical field could penetrate through. Recently, with the emerge of graphene, a new type of graphene based VFETs has been developed. With finite density of states and the weak electrostatic screening effect, graphene exhibits a field-tunable work-function and partial electrostatic transparency, it can thus function as an “active" contact with tunable graphene-channel junction, enabling entirely new transistor functions or higher device performance not previously possible. In this review, we discuss the research progresses of graphene-based VFET, including the its basic device structure, carrier transport mechanism, device performance and novel properties demonstrated.

Analytical Model for Drain Current of a Ballistic MOSFET

A simplified analytical approach within the framework of Landauer-Buttiker formalism has been employed to model the drain current in a ballistic n-channel metal oxide semiconductor field effect transistor (MOSFET) and the expression for the device threshold voltage has been obtained. To achieve ballistic operation the said MOSFET has been modeled considering low temperature (77 K) and intrinsic silicon channel for electronic motion of the charge carriers. The model incorporates quantum confinement effect, drain induced barrier lowering (DIBL) and short channel effects (SCE). Further, the effects due to surface scattering and back scattering are included in this model to obtain a near ballistic behavior. The current-voltage characteristics are compared with the available experimental results and are found to be in reasonable agreement.

Fast Blocking Effect of Gallamine on LCC Channels: Analysis Using a Truncated Kinetic Scheme

Modulation of Large-conductance cationic (LCC) channel currents through the inner nuclear membrane of rat Purkinje neurons by gallamine was estimated using analysis of the amplitude histograms. A kinetic scheme consisting of one open state and one blocked state of the channel was used. The search for optimal kinetic parameters of the truncated model was performed for the analysis of the blocking effect. The estimated rate constants of blocking and unblocking by 100 μM gallamine at –40 mV were 17880 ± ± 975 and 12790 ± 922, respectively. The obtained data show that gallamine is a fast blocker of the above channels; blocking is accompanied by ion current fluctuations suitable for the analysis using the two-state model if contribution of the events formed by intrinsic ion channel activity can be neglected.

Modification of a carbon nanotube FET compact model for digital circuit simulation

Carbon nanotube field-effect transistor (CNTFET) based circuit systems have received extensive attention due to their energy-efficiency benefits. However, there is not yet a generally accepted compact SPICE model for CNTFETs compatible with existing electronics design automation platforms. In this paper, the Stanford top gate CNTFET model is optimized through the consideration of different doping levels in source/drain as well as the simplification of an equivalent capacitance network in the intrinsic channel. Based on this, compact models are built for both top gate and wrapped gate CNTFETs. Then the DC properties and the cut-off frequency of top gate and wrapped gate CNTFETs with 15 nm channel length, and their basic logic circuits based on our modelling, are simulated by HSPICE. In the circuit simulation, we add the influence of gate-to-gate capacitance. The influences of structural parameters such as the diameter, number of CNTs and their gap on the current–voltage property, transconductance, cut-off frequency, circuit delay and power consumption are studied. Through comparison with the simulation using the Stanford model, our modelling is more suitable for the design and development of CNTFET circuits. For given parameters, the top gate CNTFETs have a larger maximum cut-off frequency and the wrapped gate CNTFETs’ saturate current is larger. Wrapped gate logic circuits have less delay but more dynamic power than top gate circuits. More CNTs in FETs with a bigger gap and shorter tube pitch lead to less circuit delay and more dynamic power.

An Improved Analog/RF and Linearity Performances with Small-Signal Parameter Extraction of Virtually Doped Recessed Source/Drain Dopingless Junctionless Transistor for Radio-Frequency Applications

A small-signal radio-frequency (RF) parameters extraction model along with analog/RF and linearity distortion performance analysis are realized for virtually doped (VD) recessed source/drain dopingless junctionless transistor (Re S/D DLJLT) via 3-D device simulations. A simple and accurate RF non-quasi-static (NQS) model is developed to directly extract the extrinsic and intrinsic parasitic components through Y-parameters in OFF and ON-state respectively. Furthermore, direct comparison of DC, analog/RF, linearity figure of merits (FOMs), and Y-parameter extractions are made with recessed source/drain junction transistor (Re S/D JT) with identical threshold voltage (Vth) and device dimensions at GHz frequency range. Virtual doping, due to charge-plasma (CP) concept, provides N+ source/drain (S/D) regions by choosing a most convenient metal work function (WF = 3.9 eV; Hafnium) at S/D. Re S/D provides reduced series resistance without an increase in gate-drain Miller capacitance leading to improved drive current. In addition, the present device uses an intrinsic channel and does not require to be doped at S/D resulting in dopingless junctionless transistor (DLJLT). For both devices, gate length (L) is taken as 30 nm, which separated into control gate (L1) and screen gate (L2) and 3-D simulations are carried out by varying control to screen gate length ratios (CSLR) to obtain optimum results. Obtained results disclose that Re S/D DLJLT provides considerably improved performances in terms of DC, analog/RF, linearity, transient, and small-signal admittance parameters over Re S/D JT due to improved drive current and reduced short channel effects (SCEs). Accordingly, for high-performance RF applications, Re S/D DLJLT may be preferred over Re S/D JT due to significantly enhanced cut-off frequency (up to 0.399 THz) and maximum oscillation frequency (up to 1.226 THz).

InAs/Si Hetero-Junction Channel to Enhance the Performance of DG-TFET with Graphene Nanoribbon: an Analytical Model

In this paper, a new two-dimensional analytical model for our proposed InAs/Si based double-gate dual-metal tunnel field-effect transistor (DG-TFET) with graphene nano-ribbon is presented. Incorporating group III-V material in source – channel junction, which in turn forms heterojunction results better device performance. Moreover, thin graphene nano-ribbon placed over intrinsic channel can tune the energy gap to larger extent, which supports better band-to-band (B2B) tunneling in our model. Direct tunneling model is used for Indium Arsenide (InAs), since it is direct bandgap material. Obtained Vth as 0.19 V, sub-threshold swing (SS) as 20.76 mV/decade and ION/IOFF ratio as 108 for the case of InAs/Si DG-TFET with graphene nano-ribbon shows an improvement of 48%, 36% and 10 decades respectively compared to conventional all-Si DG-TFET. Using 2-D TCAD numerical device simulator the proposed device model is designed and validated well with analytical data.

Tubular graphene-supported nanoparticulate manganese carbodiimide as a free-standing high-energy and high-rate anode for lithium ion batteries

Combination of high-energy density and high-power density is highly pursued in the development of advanced lithium ion batteries (LIBs). In this paper, we fabricate a free-standing anode composed of tubular graphene-supported nanoparticulate manganese carbodiimide (TG/MnNCN) for high-energy and high-power LIBs. MnNCN nanoparticles conformally coated three-dimensional TG with high surface area provide abundant active sites for electrochemical reaction and the high conductivity of TG facilitates intrinsic electron pathways and efficient ion transport channels. More importantly, the non-covalent π-π interaction between NCN group and graphene is beneficial for interfacial charge transport. Consequently, the TG/MnNCN anode exhibits a high areal capacity of 9.8 mA h cm−2 at 0.5 mA cm−2 and a high rate capacity of 3.5 mA h cm−2 at 50 mA cm−2 even at a high mass loading of up to 10 mg cm−2. Excitingly, the TG/MnNCN anode also presents impressive performance in Li-ion full cell (coupled with LiCoO2 cathode) with an outstanding energy density (15.08 mWh cm−2 and 343 Wh kg−1) and power density (378.5 mW cm−2 and 8.7 kW kg−1), indicating the potential for high-energy and high-power LIB applications.

(Keynote) Fully-Depleted SOI Technology for High-Power RF Applications

FDSOI has shown its benefits, compared to other planar bulk technologies, in low power applications by a better electrostatic control, a reduction in leakage currents and device variability. Thanks to the isolation box in the substrate and the intrinsic channel, the parasitic capacitances are also reduced significantly, including the capacitance between source and drain, and between drain and body. These features help to boost the transistors’ RF performance. The published data shows the measured fT (cut-off frequency) and fMAX (maximum oscillation frequency) of RFMOS in FDSOI processes reach 400 GHz, which is the highest among all advanced CMOS nodes. Moreover, by the process construction (gate-first vs. gate-last), the gate resistance of the transistors in FDSOI processes is smaller, which is beneficial to their RF noise performance. These benefits have been used for small-signal RF blocks in Front-end modules, e.g. LNA, VCO and mixers.In this work, the FDSOI capability for the large-signal RF blocks consisting of integrated power amplifiers (PA) is explored. In previous mobile generations (3G/4G), the base stations need to deliver the peak power more than 100 W, which is solely enabled by GaN or GaAs technologies. Their corresponding handsets also need to transmit a few Watts, which is out of the reach of CMOS-based PA. By moving to massive MIMO with a large number of antennas, the power per RF PA is reduced significantly for both base-stations and handsets in 5G network, with the PMAX per PA varying from 20 dBm to 25 dBm. Such sub-Watt power range opens the opportunities for making silicon-based RF PA, enabling a much larger scale of RF Front-end modules integration. In this paper, two key aspects to make the FDSOI process possible for high-power RF applications in 5G are presented. First, it shows the development of critical active and passive components of high-breakdown and high RF-performance. Second, the 4-port RF test structure designs and in-house characterization to explore the capability of back-bias on RF performance are discussed.Regarding the high-voltage transistors, 3.3V and 5V RF LDMOS have been designed and fabricated without any additional dedicated mask in a sub-28nm FDSOI process. The device was constructed in a non-SOI area. A record high RF-performance, with fT larger than 50 GHz for 5V LDMOS and 100 GHz for 3.3V device, has been achieved. For passive elements, 7V fringe capacitators, inductors and transformers have been developed. The fringe capacitors show their robustness at 7V, with best-in-class quality factor at both 5 GHz and 30 GHz. The matching performance of these capacitors are comparable to the best MOM capacitor mismatch performance in other modern CMOS technologies, which makes them also suitable for high-precision signal processing and filtering. Inductors and transformers have been designed in top 3 metal layers to have state-of-the-art quality factors. An excellent matching between RF measurements and EM simulations has been obtained for these passive elements. Such matching proves that the performance of the passive devices is very well predictable, enabling full design optimization for fringe capacitors and transformers / inductors.To capture the impact of back-bias on RF performance, and facilitate the RF model against silicon validation in the presence of back-bias, this paper shows a 4-port test structure design (GSGSG). The RF measurements for an RFMOS with a back-bias varying from strong reverse to forward are discussed. These results initiate various scenarios for using back-bias in RF applications, e.g. reducing the supply voltage to have the same RF performance, or extending the maximum current density at the same peak fT to have enough RF power.In summary, this paper shows the development of high-voltage RF active and passive devices in a sub-28nm FDSOI process, which are required for building integrated RF power amplifiers at Watt-level in high-performance cost-effective RF front-end ICs. The 3.3V / 5V RF-LDMOS with a cutoff frequency beyond 100GHz has been achieved in silicon, which brings a breakthrough for RF PA designs, both at sub-6GHz and 28GHz. For passive devices, by combining the novel RF design with an RF-compatible metal stack and accurate EM simulation, a record high Q-factor for a 7V-fringe capacitor, a 2-way transformer and 8-shaped inductors are obtained. The developed 4-port measurement for GSGSG structures has been proven as an indispensable tool for RF-FDSOI. These results show FDSOI process can be comparable to RF-HV-centric non-CMOS processes, e.g. SiGe and GaAs, for Watt-level power RF applications.

Influence of the Biomaterial Thickness in a Dielectrically Charged Modulated Fringing Field Bio-Tunnel-FET Device

The biosensor market is expected to increase more than 40% in 5 years ( 2019 to 2024) due to the versatile of these devices (1). Many research groups are studying new types and optimizations of these devices and the tunnel field-effect transistors (TFET) have attracted the interest due to the many advantages of these devices (2).Figure 1 shows the Bio-TFET cross section which has been simulated with TCAD Sentaurus (3). The proposed device has a gate length (LG), equivalent gate oxide thickness (tox) and channel silicon thickness (tSi) of 40 nm, 1 nm and 10 nm. The drain underlap (LUD) is variable in the range of 1 to 100 nm. The uniform doping profile of the device consists of a source and drain doping concentration of 1020 atom/cm3 of boron and arsenic, respectively. An intrinsic channel with 1015 atom/cm3 of boron. The gate electrode has a workfunction of 4.7 eV. The main models incorporated in the simulation were the bandgap narrowing (BGN), Shockley Read Hall recombination (SRH) and the nonlocal band-to-band tunneling (BTBT). In the drain underlap region is deposited a biomaterial for biosensing purposes. This material has a dielectric constant (k, where ε=k*ε0) of 1 (air), 2.1 (Streptavidin), 3.57 (APTES), 8 (Anti-Iris antibody) and 10 (Isoquinoline) (4).Figure 2 shows the Bio-TFET transfer characteristics. The ambipolar region is a parasitic tunneling current that occurs for negative gate bias (VG) for nTFET at drain to channel region. In order to decrease this effect a drain underlap (LUD) is performed at the device (5). However, when the biomaterial dielectric constant (k) increases, the ambipolar current also increases orders of magnitude, meaning that the device is very susceptible to k variation in the biomaterial region and can be used for biosensing of different types of biomolecules with a distinct k. In order to quantify the influence of change in k in the biomaterial region the equation in terms of ID: Sensitivity = ΔID/ID(Ref.) was used. Where ΔID represents the difference between the drain current of biosensing (output), e.g., the drain current with the presence of biomaterial ID(Bio) and the drain current of reference ID (Ref.) (input), e.g., drain current without biomaterial ID (k=1) . Both for a fixed value of gate voltage (VG = -2 V) in the ambipolar region. Fig.3 shows the sensitivity of the device as a function of LUD for different k values. The maximum sensitivity occurs for a LUD = 30 nm for all range of k values. The sensitivity increases for higher k as reported in (6). Another parameter that is important for sensing is the dimension of the target. Many biomolecules have different types, e.g., spherical, ellipsoidal or elongated (7). Therefore, the study of the parameter is fundamental for the functional operation of the device. In Fig.4 the sensitivity is analyzed as a function of biomaterial thickness (tBio) for a fixed value of LUD=30nm. With the rising of tBio and k the sensitivity increases, i.e., exceeding 2 orders of magnitude comparing tBio = 10nm and tBio = 30 nm for k = 10. This increment on sensitivity is due to the tunneling length lowering, as can be noticed in Fig.5. The tunneling length decrease from 5.7 nm (tBio= 10 nm) to 9.5 nm (tBio = 30 nm), both for k = 10 and fixed energy of - 1 eV. The lowering of the tunneling length increases the ambipolar current ID(Bio) that enhances the sensitivity of the device. An important consideration for the biosensing process is the charge on the biomaterial that affect the tunneling current and therefore affect the sensitivity of the device. In Fig. 6, the sensitivity is studied as in the function of positive fixed charges in the range of 1010 to 1012 cm-2. The sensitivity increases for thicker values of tBio. This is due to the higher effect of the fringing field in the region. As tBio increase the effect of fringing field increases in the biomaterial region and as consequence, the device becomes more sensible with the presence of charges.The study of charges and biomaterial thickness in a dielectrically modulated fringing field Bio-TFET was performed in this work. The device shows high sensitivity with the increase of tBio in the range studied in this work. Although, the effect of fixed charges is more notable for thicker tBio. Then, the tBio thickness shows a high impact in the sensing of the device. Figure 1

Intrinsic and Synaptic Properties Shaping Diverse Behaviors of Neural Dynamics.

The majority of neurons in the neuronal system of the brain have a complex morphological structure, which diversifies the dynamics of neurons. In the granular layer of the cerebellum, there exists a unique cell type, the unipolar brush cell (UBC), that serves as an important relay cell for transferring information from outside mossy fibers to downstream granule cells. The distinguishing feature of the UBC is that it has a simple morphology, with only one short dendritic brush connected to its soma. Based on experimental evidence showing that UBCs exhibit a variety of dynamic behaviors, here we develop two simple models, one with a few detailed ion channels for simulation and the other one as a two-variable dynamical system for theoretical analysis, to characterize the intrinsic dynamics of UBCs. The reasonable values of the key channel parameters of the models can be determined by analysis of the stability of the resting membrane potential and the rebound firing properties of UBCs. Considered together with a large variety of synaptic dynamics installed on UBCs, we show that the simple-structured UBCs, as relay cells, can extend the range of dynamics and information from input mossy fibers to granule cells with low-frequency resonance and transfer stereotyped inputs to diverse amplitudes and phases of the output for downstream granule cells. These results suggest that neuronal computation, embedded within intrinsic ion channels and the diverse synaptic properties of single neurons without sophisticated morphology, can shape a large variety of dynamic behaviors to enhance the computational ability of local neuronal circuits.

Packaged Microbubble Resonator for Versatile Optical Sensing

Microbubble whispering-gallery resonator with the intrinsic microfluidic channel is a promising platform for biochemical sensing due to their ultrahigh quality ( Q ) factor and ultralow detection limit. In this work, we realize a packaged microbubble resonator (PMBR) of ultrahigh- Q factor ( $\sim\!3.52\times 10^6$ ) in a moisture curable polymer for practical applications. The long-term stability and thermal response of a PMBR are measured. Further, we demonstrate the dynamic hydrogel gelation transition from hydrophilic to hydrophobic state by detecting the resonant wavelength shift and mode broadening in a filled PMBR simultaneously. The refractive index changes of hydrogel during the transition is explicitly modelled. Our work shows the versatility of PMBR for practical optical sensing and may open a new route to microfluidic dynamic reaction.

Charge transfer states in phycobilisomes

Phycobilisomes (PBs) absorb light and supply downstream photosynthetic processes with excitation energy in many cyanobacteria and algae. In response to a sudden increase in light intensity, excess excitation energy is photoprotectively dissipated in PBs by means of the orange carotenoid protein (OCP)-related mechanism or via a light-activated intrinsic decay channel. Recently, we have identified that both mechanisms are associated with far-red emission states. Here, we investigate the far-red states involved with the light-induced intrinsic mechanism by exploring the energy landscape and electro-optical properties of the pigments in PBs. While Stark spectroscopy showed that the far-red states in PBs exhibit a strong charge-transfer (CT) character at cryogenic temperatures, single molecule spectroscopy revealed that CT states should also be present at room temperature. Owing to the strong environmental sensitivity of CT states, the knowledge gained from this study may contribute to the design of a new generation of fluorescence markers.

Arsenic Uptake and Accumulation Mechanisms in Rice Species.

Rice consumption is a source of arsenic (As) exposure, which poses serious health risks. In this study, the accumulation of As in rice was studied. Research shows that As accumulation in rice in Taiwan and Bangladesh is higher than that in other countries. In addition, the critical factors influencing the uptake of As into rice crops are defined. Furthermore, determining the feasibility of using effective ways to reduce the accumulation of As in rice was studied. AsV and AsIII are transported to the root through phosphate transporters and nodulin 26-like intrinsic channels. The silicic acid transporter may have a vital role in the entry of methylated As, dimethylarsinic acid (DMA) and monomethylarsonic acid (MMA), into the root. Amongst As species, DMA(V) is particularly mobile in plants and can easily transfer from root to shoot. The OsPTR7 gene has a key role in moving DMA in the xylem or phloem. Soil properties can affect the uptake of As by plants. An increase in organic matter and in the concentrations of sulphur, iron, and manganese reduces the uptake of As by plants. Amongst the agronomic strategies in diminishing the uptake and accumulation of As in rice, using microalgae and bacteria is the most efficient.

Dimension Scaling Effects on Conduction and Low Frequency Noise Characteristics of ITO-Stabilized ZnO Thin Film Transistors

Conduction characteristics and low frequency noises in ITO-stabilized ZnO thin film transistors (TFTs) with constant channel width (W=50 μm) and different channel lengths (L=5, 10, 25, 50 and 100 μm) are measured and analysis. Firstly, dependences of threshold voltage and field effect mobility on channel length are examined. With decreasing channel length, the threshold voltage shifts to the negative direction which may attribute to carrier diffusion from source/drain to the intrinsic device channel. In addition, significant degradation of field effect mobility is observed in short channel device which are induced by the presence of series contact resistance. The value of contact resistance has also been extracted. Secondly, the drain current noise power spectral densities (S ID ) are measured at varied effective gate voltages. The measured noises follow a 1/f γ and y is about -1.1. Moreover, the normalized noises (S ID /I ds ) are dependent linearly on the inverse of channel length and the slope is about -0.75. Finally, the dominant mechanism of low frequency noise in ITO-stabilized ZnO thin film transistor are examined. The slope of normalized noise against effective gate voltage are extracted, which are varied from -1.03 to -1.84 with decreasing channel length and thus it indicates that ITO-stabilized ZnO TFTs varied from bulk dominated devices to interface dominated devices. By using of ΔN-Δμ model, the normalized noises are simulated by considering of contact resistance. Several noise parameters (flat-band voltage noise spectral density, etc) are extracted and analysis.

TRPC5 channel instability induced by depalmitoylation protects striatal neurons against oxidative stress in Huntington's disease

Protein S-palmitoylation, the covalent lipid modification of the side chain of Cys residues with the 16‑carbon fatty acid palmitate, is the most common acylation, and it enhances the membrane stability of ion channels. This post-translational modification (PTM) determines a functional mechanism of ion channel life cycle from maturation and membrane trafficking to localization. Especially, neurodevelopment is regulated by balancing the level of synaptic protein palmitoylation/depalmitoylation. Recently, we revealed the pathological role of the transient receptor potential canonical type 5 (TRPC5) channel in striatal neuronal loss during Huntington's disease (HD), which is abnormally activated by oxidative stress. Here, we report a mechanism of TRPC5 palmitoylation at a conserved cysteine residue, that is critical for intrinsic channel activity. Furthermore, we identified the therapeutic effect of TRPC5 depalmitoylation by enhancing the TRPC5 membrane instability on HD striatal cells in order to lower TRPC5 toxicity.Collectively, these findings suggest that controlling S-palmitoylation of the TRPC5 channel as a potential risk factor can modulate TRPC5 channel expression and activity, providing new insights into a therapeutic strategy for neurodegenerative diseases.

Conformational Changes in the 5-HT3A Receptor Extracellular Domain Measured by Voltage-Clamp Fluorometry

The 5-hydroxytryptamine (5-HT) type 3 receptor is a member of the cysteine (Cys)-loop receptor super family of ligand-gated ion channels in the nervous system and is a clinical target in a range of diseases. The 5-HT3 receptor mediates fast serotonergic neurotransmission by undergoing a series of conformational changes initiated by ligand binding that lead to the rapid opening of an intrinsic cation-selective channel. However, despite the availability of high-resolution structures of a mouse 5-HT3 receptor, many important aspects of the mechanistic basis of 5-HT3 receptor function and modulation by drugs remain poorly understood. In particular, there is little direct evidence for the specific conformational changes predicted to occur during ligand-gated channel activation and desensitization. In the present study, we used voltage-clamp fluorometry (VCF) to measure conformational changes in regions surrounding the orthosteric binding site of the human 5-HT3A (h5-HT3A) receptor during binding of 5-HT and different classes of 5-HT3 receptor ligands. VCF utilizes parallel measurements of receptor currents with photon emission from fluorescent reporter groups covalently attached to specific positions in the receptor structure. Reporter groups that are highly sensitive to the local molecular environment can, in real time, report conformational changes as changes in fluorescence that can be correlated with changes in receptor currents reporting the functional states of the channel. Within the loop C, D, and E regions that surround the orthosteric binding site in the h5-HT3A receptor, we identify positions that are amenable to tagging with an environmentally sensitive reporter group that reports robust fluorescence changes upon 5-HT binding and receptor activation. We use these reporter positions to characterize the effect of ligand binding on the local structure of the orthosteric binding site by agonists, competitive antagonists, and allosterically acting channel activators. We observed that loop C appears to show distinct fluorescence changes for ligands of the same class, while loop D reports similar fluorescence changes for all ligands binding at the orthosteric site. In contrast, the loop E reporter position shows distinct changes for agonists, antagonists, and allosteric compounds, suggesting the conformational changes in this region are specific to ligand function. Interpretation of these results within the framework of current models of 5-HT3 and Cys-loop mechanisms are used to expand the understanding of how ligand binding in Cys-loop receptors relates to channel gating. SIGNIFICANCE STATEMENT: The 5-HT3 receptor is an important ligand-gated ion channel and drug target in the central and peripheral nervous system. Determining how ligand binding induced conformational changes in the receptor is central for understanding the structural mechanisms underlying 5-HT3 receptor function. Here, we employ voltage-gated fluorometry to characterize conformational changes in the extracellular domain of the human 5-HT3 receptor to identify intrareceptor motions during binding of a range of 5-HT3 receptor agonists and antagonists.

β-Arrestin2 regulates the rapid component of delayed rectifier K+ currents and cardiac action potential of guinea pig cardiomyocytes after adrenergic stimulation

A decrease in the rapid component of delayed rectifier potassium current (IKr) during chronic heart failure (CHF) prolongs action potential (AP), and plays a key rolein the pathogenesis of ventricular arrhythmias. β-Arrestin2 has been shown to restore the inotropic reserve of β-adrenergic regulation, but little or nothing is known about its effect on intrinsic channel. This study investigated the role of β-arrestin2 in the regulation of cardiac hERG/IKr potassium channel and AP during chronic adrenergic stimulation. Single left ventricular myocytes were isolated from guinea pig heart, and were transfected with adenovirus encoding β-arrestin2, or β-arrestin2 siRNA or an empty adenovirus. Cell cultures containing 10 nM isoproterenol, 1 nM phenylephrine or vehicle alone (control medium) were electro-physiologically examined after 48 h of incubation. Action potential duration at 50 and 90 % of repolarization (APD50 and APD90) were measured using whole-cell patch-clamp recording. Sustained adrenergic stimulation significantly reduced the density of the IKr current (p < 0.001). β-Arrestin2 expression in cell cultures treated with isoproterenol or phenylephrine was significantly downregulated after adrenergic stimulation (p < 0.001). Overexpression of β-arrestin2 significantly attenuated isoproterenol or phenylephrine-induced reduction in IKr current. It also prevented the phenylephrine-induced prolongation of AP (p < 0.05 for APD50 and p < 0.001 for APD90), but did not significantly affect AP profile after exposure of the cardiomyocytes to isoproterenol (p > 0.05). Therefore, Increased levels of β-Arrestin2 weaken dysregulation of IKr current and prevent excessive AP prolongation, making it an effective anti-arrhythmic strategy.

5-HT<sub>3</sub> receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The 5-HT3 receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on 5-Hydroxytryptamine (serotonin) receptors [66]) is a ligand-gated ion channel of the Cys-loop family that includes the zinc-activated channels, nicotinic acetylcholine, GABAA and strychnine-sensitive glycine receptors. The receptor exists as a pentamer of 4TM subunits that form an intrinsic cation selective channel [5]. Five human 5-HT3 receptor subunits have been cloned and homo-oligomeric assemblies of 5-HT3A and hetero-oligomeric assemblies of 5-HT3A and 5-HT3B subunits have been characterised in detail. The 5-HT3C (HTR3C, Q8WXA8), 5-HT3D (HTR3D, Q70Z44) and 5-HT3E (HTR3E, A5X5Y0) subunits [83, 122], like the 5-HT3B subunit, do not form functional homomers, but are reported to assemble with the 5-HT3A subunit to influence its functional expression rather than pharmacological profile [124, 63, 157]. 5-HT3A, -C, -D, and -E subunits also interact with the chaperone RIC-3 which predominantly enhances the surface expression of homomeric 5-HT3A receptor [157]. The co-expression of 5-HT3A and 5-HT3C-E subunits has been demonstrated in human colon [82]. A recombinant hetero-oligomeric 5-HT3AB receptor has been reported to contain two copies of the 5-HT3A subunit and three copies of the 5-HT3B subunit in the order B-B-A-B-A [7], but this is inconsistent with recent reports which show at least one A-A interface [96, 150]. The 5-HT3B subunit imparts distinctive biophysical properties upon hetero-oligomeric 5-HT3AB versus homo-oligomeric 5-HT3A recombinant receptors [32, 41, 56, 85, 139, 129, 79], influences the potency of channel blockers, but generally has only a modest effect upon the apparent affinity of agonists, or the affinity of antagonists ([17], but see [41, 30, 35]) which may be explained by the orthosteric binding site residing at an interface formed between 5-HT3A subunits [96, 150]. However, 5-HT3A and 5-HT3AB receptors differ in their allosteric regulation by some general anaesthetic agents, small alcohols and indoles [138, 135, 71]. The potential diversity of 5-HT3 receptors is increased by alternative splicing of the genes HTR3A and E [64, 19, 124, 123, 120]. In addition, the use of tissue-specific promoters driving expression from different transcriptional start sites has been reported for the HTR3A, HTR3B, HTR3D and HTR3E genes, which could result in 5-HT3 subunits harbouring different N-termini [152, 79, 120]. To date, inclusion of the 5-HT3A subunit appears imperative for 5-HT3 receptor function.

GABA<sub>A</sub> receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The GABAA receptor is a ligand-gated ion channel of the Cys-loop family that includes the nicotinic acetylcholine, 5-HT3 and strychnine-sensitive glycine receptors. GABAA receptor-mediated inhibition within the CNS occurs by fast synaptic transmission, sustained tonic inhibition and temporally intermediate events that have been termed ‘GABAA, slow’ [41]. GABAA receptors exist as pentamers of 4TM subunits that form an intrinsic anion selective channel. Sequences of six α, three β, three γ, one δ, three ρ, one ε, one π and one θ GABAA receptor subunits have been reported in mammals [273, 232, 231, 278]. The π-subunit is restricted to reproductive tissue. Alternatively spliced versions of many subunits exist (e.g. α4- and α6- (both not functional) α5-, β2-, β3- and γ2), along with RNA editing of the α3 subunit [67]. The three ρ-subunits, (ρ1-3) function as either homo- or hetero-oligomeric assemblies [354, 46]. Receptors formed from ρ-subunits, because of their distinctive pharmacology that includes insensitivity to bicuculline, benzodiazepines and barbiturates, have sometimes been termed GABAC receptors [354], but they are classified as GABAA receptors by NC-IUPHAR on the basis of structural and functional criteria [14, 232, 231].Many GABAA receptor subtypes contain α-, β- and γ-subunits with the likely stoichiometry 2α.2β.1γ [164, 232]. It is thought that the majority of GABAA receptors harbour a single type of α- and β -subunit variant. The α1β2γ2 hetero-oligomer constitutes the largest population of GABAA receptors in the CNS, followed by the α2β3γ2 and α3β3γ2 isoforms. Receptors that incorporate the α4- α5-or α6-subunit, or the β1-, γ1-, γ3-, δ-, ε- and θ-subunits, are less numerous, but they may nonetheless serve important functions. For example, extrasynaptically located receptors that contain α6- and δ-subunits in cerebellar granule cells, or an α4- and δ-subunit in dentate gyrus granule cells and thalamic neurones, mediate a tonic current that is important for neuronal excitability in response to ambient concentrations of GABA [205, 268, 79, 17, 283]. GABA binding occurs at the β+/α- subunit interface and the homologous γ+/α- subunits interface creates the benzodiazepine site. A second site for benzodiazepine binding has recently been postulated to occur at the α+/β- interface ([250]; reviewed by [277]). The particular α-and γ-subunit isoforms exhibit marked effects on recognition and/or efficacy at the benzodiazepine site. Thus, receptors incorporating either α4- or α6-subunits are not recognised by ‘classical’ benzodiazepines, such as flunitrazepam (but see [351]). The trafficking, cell surface expression, internalisation and function of GABAA receptors and their subunits are discussed in detail in several recent reviews [48, 136, 184, 311] but one point worthy of note is that receptors incorporating the γ2 subunit (except when associated with α5) cluster at the postsynaptic membrane (but may distribute dynamically between synaptic and extrasynaptic locations), whereas as those incorporating the d subunit appear to be exclusively extrasynaptic. NC-IUPHAR [14, 232] class the GABAA receptors according to their subunit structure, pharmacology and receptor function. Currently, eleven native GABAA receptors are classed as conclusively identified (i.e., α1β2γ2, α1βγ2, α3βγ2, α4βγ2, α4β2δ, α4β3δ, α5βγ2, α6βγ2, α6β2δ, α6β3δ and ρ) with further receptor isoforms occurring with high probability, or only tentatively [232, 231]. It is beyond the scope of this Guide to discuss the pharmacology of individual GABAA receptor isoforms in detail; such information can be gleaned in the reviews [14, 91, 164, 169, 140, 273, 212, 232, 231] and [8, 7]. Agents that discriminate between α-subunit isoforms are noted in the table and additional agents that demonstrate selectivity between receptor isoforms, for example via β-subunit selectivity, are indicated in the text below. The distinctive agonist and antagonist pharmacology of ρ receptors is summarised in the table and additional aspects are reviewed in [354, 46, 141, 219].Several high-resolution cryo-electron microscopy structures have been described in which the full-length human α1β3γ2L GABAA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (γ-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam [194].