Voltage-dependent Gating Research Articles

Link between the Superconducting Dome and Spin-Orbit Interaction in the (111) LaAlO_{3}/SrTiO_{3} Interface.

We measure the gate voltage (V_{g}) dependence of the superconducting properties and the spin-orbit interaction in the (111)-oriented LaAlO_{3}/SrTiO_{3} interface. Superconductivity is observed in a dome-shaped region in the carrier density-temperature phase diagram with the maxima of superconducting transition temperature T_{c} and the upper critical fields lying at the same V_{g}. The spin-orbit interaction determined from the superconducting parameters and confirmed by weak-antilocalization measurements follows the same gate voltage dependence as T_{c}. The correlation between the superconductivity and spin-orbit interaction as well as the enhancement of the parallel upper critical field, well beyond the Chandrasekhar-Clogston limit, suggest that superconductivity and the spin-orbit interaction are linked in a nontrivial fashion. We propose possible scenarios to explain this unconventional behavior.

Contact-induced doping in aluminum-contacted molybdenum disulfide

The interface between two-dimensional semiconductors and metal contacts is an important topic of research of nanoelectronic devices based on two-dimensional semiconducting materials such as molybdenum disulfide (MoS2). We report transport properties of thin MoS2 flakes in a field-effect transistor geometry with Ti/Au and Al contacts. In contrast to widely used Ti/Au contacts, the conductance of flakes with Al contacts exhibits a smaller gate-voltage dependence, which is consistent with a substantial electron doping effect of the Al contacts. The temperature dependence of two-terminal conductance for the Al contacts is also considerably smaller than for the Ti/Au contacts, in which thermionic emission and thermally assisted tunneling play a dominant role. This result is explained in terms of the assumption that the carrier injection mechanism at an Al contact is dominated by tunneling that is not thermally activated.

Controlling the bound states in a quantum-dot hybrid nanowire

Recent experiments using the quantum dot coupled to the topological superconducting nanowire [M.T. Deng et al., Science 354, 1557 (2016)}] revealed that zero-energy bound state coalesces from the Andreev bound states. Such quasiparticle states, present in the quantum dot, can be controlled by the magnetic and electrostatic means. We use microscopic model of the quantum-dot--nanowire structure to reproduce the experimental results, applying the Bogoliubov--de~Gennes technique. This is done by studying the gate voltage dependence of the various types of bound states and mutual influence between them. We show that the zero energy bound states can emerge from the Andreev bound states in topologically trivial phase and can be controlled using various means. In non-trivial topological phase we show the possible resonance between this zero energy levels with Majorana bound states. We discuss and explain this phenomena as a result of dominant spin character of discussed bound states. Presented results can be applied in experimental studies by using the proposed nanodevice.

Irritable bowel syndrome patients have SCN5A channelopathies that lead to decreased NaV1.5 current and mechanosensitivity.

The SCN5A-encoded voltage-gated mechanosensitive Na+ channel NaV1.5 is expressed in human gastrointestinal smooth muscle cells and interstitial cells of Cajal. NaV1.5 contributes to smooth muscle electrical slow waves and mechanical sensitivity. In predominantly Caucasian irritable bowel syndrome (IBS) patient cohorts, 2-3% of patients have SCN5A missense mutations that alter NaV1.5 function and may contribute to IBS pathophysiology. In this study we examined a racially and ethnically diverse cohort of IBS patients for SCN5A missense mutations, compared them with IBS-negative controls, and determined the resulting NaV1.5 voltage-dependent and mechanosensitive properties. All SCN5A exons were sequenced from somatic DNA of 252 Rome III IBS patients with diverse ethnic and racial backgrounds. Missense mutations were introduced into wild-type SCN5A by site-directed mutagenesis and cotransfected with green fluorescent protein into HEK-293 cells. NaV1.5 voltage-dependent and mechanosensitive functions were studied by whole cell electrophysiology with and without shear force. Five of 252 (2.0%) IBS patients had six rare SCN5A mutations that were absent in 377 IBS-negative controls. Six of six (100%) IBS-associated NaV1.5 mutations had voltage-dependent gating abnormalities [current density reduction (R225W, R433C, R986Q, and F1293S) and altered voltage dependence (R225W, R433C, R986Q, G1037V, and F1293S)], and at least one kinetic parameter was altered in all mutations. Four of six (67%) IBS-associated SCN5A mutations (R225W, R433C, R986Q, and F1293S) resulted in altered NaV1.5 mechanosensitivity. In this racially and ethnically diverse cohort of IBS patients, we show that 2% of IBS patients harbor SCN5A mutations that are absent in IBS-negative controls and result in NaV1.5 channels with abnormal voltage-dependent and mechanosensitive function. NEW & NOTEWORTHY The voltage-gated Na+ channel NaV1.5 contributes to smooth muscle physiology and electrical slow waves. In a racially and ethnically mixed irritable bowel syndrome cohort, 2% had mutations in the NaV1.5 gene SCN5A. These mutations were absent in irritable bowel syndrome-negative controls. Most mutant NaV1.5 channels were loss of function in voltage dependence or mechanosensitivity.

Extended beta distributions open the access to fast gating in bilayer experiments-assigning the voltage-dependent gating to the selectivity filter.

Lipid bilayers provide many benefits for ion channel recordings, such as control of membrane composition and transport molecules. However, they suffer from high membrane capacitance limiting the bandwidth and impeding analysis of fast gating. This can be overcome by fitting the deviations of the open‐channel noise from the baseline noise by extended beta distributions. We demonstrate this analysis step‐by‐step by applying it to the example of viral K+ channels (Kcv), from the choice of the gating model through the fitting process, validation of the results, and what kinds of results can be obtained. These voltage sensor‐less channels show profoundly voltage‐dependent gating with dwell times in the closed state of about 50 μs. Mutations assign it to the selectivity filter.

Ambi-polar anomalous Nernst effect in a magnetic topological insulator

We report electromagnetic and thermomagnetic transport studies on a magnetic topological insulator thin film Cr0.15(Bi0.1Sb0.9)1.85Te3 grown by molecular beam epitaxy. The temperature and gate voltage dependence of the anomalous Hall effect exhibits the typical behavior of a quantum anomalous Hall insulator. The anomalous Nernst effect (ANE) shows a sign reversal when the Fermi level is tuned across the charge neutrality point of the surface Dirac cone. We show that the ambi-polar behavior of the ANE can be explained by the semiclassical Mott relation, in conjunction with the ambi-polar Dirac band structure.

Weak antilocalization induced by Rashba spin-orbit interaction in layered III-VI compound semiconductor GaSe thin films

Magnetoconductance (MC) at low temperature was measured to investigate spin-related transport affected by spin-orbit interaction (SOI) in III-VI compound $n$-type GaSe thin films. Results reveal that MC shows weak antilocalization (WAL). Its temperature and gate voltage dependences reveal that the dominant spin relaxation is governed by the D'yakonov-Perel' mechanism associated with the Rashba SOI. The estimated Rashba SOI strength in GaSe is much stronger than that of III-V compound GaAs quantum wells, although the energy gap and spin split-off band in GaSe closely resemble those in GaAs. The angle dependence of WAL amplitude in the in-plane magnetic field direction is almost isotropic. This isotropy indicates that the strength of the Dresselhaus SOI is negligible compared with the Rashba SOI strength. The SOI effect in $n$-GaSe thin films differs greatly from those of III-V compound semiconductors and transition-metal dichalcogenides.

Field Effect of a Chemically Assembled Fe3O4 Nanocrystal Film Single‐Electron Transistor

The gate voltage dependence of the source‐drain current of a chemically assembled Fe3O4 nanocrystal film single‐electron transistor reflects the energy level splitting of the minority spin 3d band due to two‐electron Coulomb repulsion in each nanocrystal. Using the Langmuir–Blodgett technique, a Fe3O4 nanocrystal self‐assembled film was deposited on a quartz substrate where a three‐terminal electrode made of Au was prefabricated. At 300 K in a magnetic field of 0.2 T, the source‐drain current peaked near the source‐drain bias voltage of 100 V at a gate voltage of +1 to +3 V. At a bias voltage of 100 V, a gate voltage of +1 V amplified the current 13 times more than at a gate voltage of 0 V. Upon increasing the gate voltage to +5 V, the amplification of the current declined to less than three times more than at 0 V. At the optimized gate voltage, by adjusting the empty upper band energy of each Fe3O4 nanocrystal over the gate electrode to match the filled lower band energy outside of the gate electrode, the tunneling current can be greatly increased, because electron transport via the empty state of each nanocrystal over the gate electrode requires no extra energy cost.

Negatively charged residues in the first extracellular loop of the L-type CaV1.2 channel anchor the interaction with the CaVα2δ1 auxiliary subunit

Voltage-gated L-type CaV1.2 channels in cardiomyocytes exist as heteromeric complexes. Co-expression of CaVα2δ1 with CaVβ/CaVα1 proteins reconstitutes the functional properties of native L-type currents, but the interacting domains at the CaV1.2/CaVα2δ1 interface are unknown. Here, a homology-based model of CaV1.2 identified protein interfaces between the extracellular domain of CaVα2δ1 and the extracellular loops of the CaVα1 protein in repeats I (IS1S2 and IS5S6), II (IIS5S6), and III (IIIS5S6). Insertion of a 9-residue hemagglutinin epitope in IS1S2, but not in IS5S6 or in IIS5S6, prevented the co-immunoprecipitation of CaV1.2 with CaVα2δ1. IS1S2 contains a cluster of three conserved negatively charged residues Glu-179, Asp-180, and Asp-181 that could contribute to non-bonded interactions with CaVα2δ1. Substitutions of CaV1.2 Asp-181 impaired the co-immunoprecipitation of CaVβ/CaV1.2 with CaVα2δ1 and the CaVα2δ1-dependent shift in voltage-dependent activation gating. In contrast, single substitutions in CaV1.2 in neighboring positions in the same loop (179, 180, and 182–184) did not significantly alter the functional up-regulation of CaV1.2 whole-cell currents. However, a negatively charged residue at position 180 was necessary to convey the CaVα2δ1-mediated shift in the activation gating. We also found a more modest contribution from the positively charged Arg-1119 in the extracellular pore region in repeat III of CaV1.2. We conclude that CaV1.2 Asp-181 anchors the physical interaction that facilitates the CaVα2δ1-mediated functional modulation of CaV1.2 currents. By stabilizing the first extracellular loop of CaV1.2, CaVα2δ1 may up-regulate currents by promoting conformations of the voltage sensor that are associated with the channel's open state.

Temperature dependence of universal conductance fluctuation due to development of weak localization in graphene

The temperature effect of quantum interference on resistivity is examined in monolayer graphene, with experimental results showing that the amplitude of the conductance fluctuation increases as temperature decreases. We find that this behavior can be attributed to the decrease in the inelastic scattering (dephasing) rate, which enhances the weak localization (WL) correction to resistivity. Following a previous report that explained the relationship between the universal conductance fluctuation (UCF) and WL regarding the gate voltage dependence (Terasawa et al., 2017) [19], we propose that the temperature dependence of the UCF in monolayer graphene can be interpreted by the WL theory.

(Invited) Dipoles in Gate-Stack/FDSOI Structure

State of the art CMOS gate stacks as well as devices are more and more complex with many possible technological options. This paper addresses the measurement and the understanding of several dipoles which may be present in the FDSOI gate stack (generation 28-14-10 nm). These dipoles are namely the intrinsic SiO2/high-k dipole, the dipoles induced by Lanthanum and Aluminum doping to change the effective workfunction, and the Germanium induced dipole in the case of SiGe channel. Some reliability studies (NBTI) will be presented on these stacks, leading to an interesting regard on physical mechanisms. The paper first review the objectives and the effects of Aluminum and Lanthanum doping in the gate stack. Aluminum and Lanthanum are used for effective workfunction engineering, shifting the effective workfunction respectively towards P+ and towards N+. This shift has been shown to be due not to charges created inside the stack but instead to the modification of the built in dipole at the bottom oxide-high k (here HfO2) interface. Globally speaking, the observed shift is around 30 to 60 meV per 10E14 at/cm2 of introduced species in the stack, only a part of them being active in the dipole formation [1]. Theoretical investigations through ab-initio simulations will be presented to explain this phenomena. Using this technology, a shift of several hundred millivolts can be obtained to adjust Vt for NMOS and PMOS in an industrial way. Notice that depending on the architecture and the sequential order of doping of NMOS and PMOS, both type of dopants may be present in each kind of device, NMOS and PMOS. Due to this observation, the effect of both Aluminum and Lanthanum is considered studied in this paper for NMOS and PMOS. Previous study on Bulk CMOS on SiGe concluded to the presence of a dipole at the interface SiO2/SiGe [2]. This dipole was shown to shift by around 150 mV the SiGe the band structure respectively to an ideal case without dipole. In the case of FDSOI with SiGe, SiGe exibits one interface with the high-k bottom SiO2 oxide and one interface with the SiO2 Buried oxide (BOX). Experiments made on PMOS FDSOI with SiGe channel actually evidence the two opposite dipoles at the interface SiO2bottom/SiGe and at the interface SiGe/Box [3]. This understanding must significantly improve the whole modeling of the structure. The bias temperature instabilities effects (NBTI and PBTI) induced by Lanthanum and Aluminum incorporation are then briefly discussed. An interesting theoretical case is the NBTI with La doping. When compared at same electric field, which is the usual way in literature to analyze physically the data, incorporation of La causes significant degradation of intrinsic NBTI. On the other hand comparison at the same gate voltage does not show at all the same results. The results of this work tend to evidence a physical law exhibiting a gate voltage dependence instead of an electric field dependence. This is supported by a large matrix of experiments (VGi, [La]i) [4]. The pro and contrary arguments for the two points of view will be discussed in the full paper as well as their implications on the device lifetime.

Characterization and mobility analysis of MoO3-gated diamond MOSFET

A MoO3-gated diamond metal–oxide–semiconductor field effect transistor (MOSFET) with a gate length of 40 µm was characterized. Analysis of the flat band voltage shift from the capacitance–voltage hysteresis shows quite high density of the fixed charge presents in the MoO3 layer (1.67 × 1012 cm−2), but the density of the traps brought by MoO3 layer is fairly low (1.35 × 1011 cm−2). The gate voltage dependence of the effective hole mobility was extracted and fitted by the empirical relation widely used in the silicon MOS channel. The resulting low-field mobility without vertical field degradation and the mobility degradation factor are 699 cm2/(V·s) and 1.13, respectively.

Integrative Approach with Electrophysiological and Theoretical Methods Reveals a New Role of S4 Positively Charged Residues in PKD2L1 Channel Voltage-Sensing

Numerical model-based simulations provide important insights into ion channel gating when experimental limitations exist. Here, a novel strategy combining numerical simulations with patch clamp experiments was used to investigate the net positive charges in the putative transmembrane segment 4 (S4) of the atypical, positively-shifted voltage-dependence of polycystic kidney disease 2-like 1 (PKD2L1) channel. Charge-neutralising mutations (K452Q, K455Q and K461Q) in S4 reduced gating charges, positively shifted the Boltzmann-type activation curve [i.e., open probability (Popen)-V curve] and altered the time-courses of activation/deactivation of PKD2L1, indicating that this region constitutes part of a voltage sensor. Numerical reconstruction of wild-type (WT) and mutant PKD2L1-mediated currents necessitated, besides their voltage-dependent gating parameters, a scaling factor that describes the voltage-dependence of maximal conductance, Gmax. Subsequent single-channel conductance (γ) measurements revealed that voltage-dependence of Gmax in WT can be explained by the inward-rectifying property of γ, which is greatly changed in PKD2L1 mutants. Homology modelling based on PKD2 and NaVAb structures suggest that such voltage dependence of Popen and γ in PKD2L1 could both reflect the charged state of the S4 domain. The present conjunctive experimental and theoretical approaches provide a framework to explore the undetermined mechanism(s) regulating TRP channels that possess non-classical voltage-dependent properties.

Ephaptic coupling rescues conduction failure in weakly coupled cardiac tissue with voltage-gated gap junctions.

Electrical conduction in cardiac tissue is usually considered to be primarily facilitated by gap junctions, providing a pathway between the intracellular spaces of neighboring cells. However, recent studies have highlighted the role of coupling via extracellular electric fields, also known as ephaptic coupling, particularly in the setting of reduced gap junction expression. Further, in the setting of reduced gap junctional coupling, voltage-dependent gating of gap junctions, an oft-neglected biophysical property in computational studies, produces a positive feedback that promotes conduction failure. We hypothesized that ephaptic coupling can break the positive feedback loop and rescue conduction failure in weakly coupled cardiac tissue. In a computational tissue model incorporating voltage-gated gap junctions and ephaptic coupling, we demonstrate that ephaptic coupling can rescue conduction failure in weakly coupled tissue. Further, ephaptic coupling increased conduction velocity in weakly coupled tissue, and importantly, reduced the minimum gap junctional coupling necessary for conduction, most prominently at fast pacing rates. Finally, we find that, although neglecting gap junction voltage-gating results in negligible differences in well coupled tissue, more significant differences occur in weakly coupled tissue, greatly underestimating the minimal gap junctional coupling that can maintain conduction. Our study suggests that ephaptic coupling plays a conduction-preserving role, particularly at rapid heart rates.

Post-translational palmitoylation controls the voltage gating and lipid raft association of the CALHM1 channel.

Calcium homeostasis modulator 1 (CALHM1), a new voltage-gated ATP- and Ca2+ -permeable channel, plays important physiological roles in taste perception and memory formation. Regulatory mechanisms of CALHM1 remain unexplored, although the biophysical disparity between CALHM1 gating in vivo and in vitro suggests that there are undiscovered regulatory mechanisms. Here we report that CALHM1 gating and association with lipid microdomains are post-translationally regulated through the process of protein S-palmitoylation, a reversible attachment of palmitate to cysteine residues. Our data also establish cysteine residues and enzymes responsible for CALHM1 palmitoylation. CALHM1 regulation by palmitoylation provides new mechanistic insights into fine-tuning of CALHM1 gating in vivo and suggests a potential layer of regulation in taste and memory. Emerging roles of CALHM1, a recently discovered voltage-gated ion channel, include purinergic neurotransmission of tastes in taste buds and memory formation in the brain, highlighting its physiological importance. However, the regulatory mechanisms of the CALHM1 channel remain entirely unexplored, hindering full understanding of its contribution in vivo. The different gating properties of CALHM1 in vivo and in vitro suggest undiscovered regulatory mechanisms. Here, in searching for post-translational regulatory mechanisms, we discovered the regulation of CALHM1 gating and association with lipid microdomains via protein S-palmitoylation, the only reversible lipid modification of proteins on cysteine residues. CALHM1 is palmitoylated at two intracellular cysteines located in the juxtamembrane regions of the third and fourth transmembrane domains. Enzymes that catalyse CALHM1 palmitoylation were identified by screening 23 members of the DHHC protein acyltransferase family. Epitope tagging of endogenous CALHM1 proteins in mice revealed that CALHM1 is basally palmitoylated in taste buds in vivo. Functionally, palmitoylation downregulates CALHM1 without effects on its synthesis, degradation and cell surface expression. Mutation of the palmitoylation sites has a profound impact on CALHM1 gating, shifting the conductance-voltage relationship to more negative voltages and accelerating the activation kinetics. The same mutation also reduces CALHM1 association with detergent-resistant membranes. Our results comprehensively uncover a post-translational regulation of the voltage-dependent gating of CALHM1 by palmitoylation.

Bulk-impurity induced noise in large-area epitaxial thin films of topological insulators

We report a detailed study on low-frequency 1/f-noise in large-area molecular-beam epitaxy grown thin (∼10 nm) films of topological insulators as a function of temperature, gate voltage, and magnetic field. When the Fermi energy is within the bulk valence band, the temperature dependence reveals a clear signature of generation-recombination noise in the defect states in the bulk band gap. However, when the Fermi energy is tuned to the bulk band gap, the gate voltage dependence of noise shows that the resistance fluctuations in surface transport are caused by correlated mobility-number density fluctuations due to the activated defect states present in the bulk of the topological insulator crystal with a density of Dit=3.2×1017 cm−2 eV−1. In the presence of the magnetic field, noise in these materials follows a parabolic dependence, which is qualitatively similar to mobility and charge-density fluctuation noise in non-degenerately doped trivial semiconductors. Our studies reveal that even in thin films of (Bi,Sb)2Te3 with thickness as low as 10 nm, the internal bulk defects are the dominant source of noise.

SMITten for KCNQ Channels

Over the last two decades, members of the KCNQ channel family of potassium channels (KCNQ1–5) have emerged as critical regulators of cardiac and neuronal excitability (1,2). KCNQ1 channels are the molecular determinants of the cardiac slow potassium current, IKS (1), which is partly responsible for the repolarization of the cardiac action potential. Loss-of-function variants of KCNQ1 channels lead to a rare heart condition, long QT syndrome, and gain-of-function variants lead to atrial fibrillation.

SMIT1 Modifies KCNQ Channel Function and Pharmacology by Physical Interaction with the Pore

Voltage-gated potassium channels of the KCNQ (Kv7) subfamily are essential for control of cellular excitability and repolarization in a wide range of cell types. Recently, we and others found that some KCNQ channels functionally and physically interact with sodium-dependent solute transporters, including myo-inositol transporters SMIT1 and SMIT2, potentially facilitating various modes of channel-transporter signal integration. In contrast to indirect effects such as channel regulation by SMIT-transported, myo-inositol-derived phosphatidylinositol 4,5-bisphosphate (PIP2), the mechanisms and functional consequences of the physical interaction of channels with transporters have been little studied. Here, using co-immunoprecipitation with different channel domains, we found that SMIT1 binds to the KCNQ2 pore module. We next tested the effects of SMIT1 co-expression, in the absence of extracellular myo-inositol or other SMIT1 substrates, on fundamental functional attributes of KCNQ2, KCNQ2/3, KCNQ1, and KCNQ1-KCNE1 channels. Without exception, SMIT1 altered KCNQ ion selectivity, sensitivity to extracellular K+, and pharmacology, consistent with an impact on conformation of the KCNQ pore. SMIT1 also altered the gating kinetics and/or voltage dependence of KCNQ2, KCNQ2/3, and KCNQ1-KCNE1. In contrast, SMIT1 had no effect on Kv1.1 (KCNA1) gating, ion selectivity, or pharmacology. We conclude that, independent of its transport activity and indirect regulatory mechanisms involving inositol-derived increases in PIP2, SMIT1, and likely other related sodium-dependent solute transporters, regulates KCNQ channel ion selectivity, gating, and pharmacology by direct physical interaction with the pore module.

Phosphodiesterases 3 and 4 Differentially Regulate the Funny Current, If, in Mouse Sinoatrial Node Myocytes.

Cardiac pacemaking, at rest and during the sympathetic fight-or-flight response, depends on cAMP (3′,5′-cyclic adenosine monophosphate) signaling in sinoatrial node myocytes (SAMs). The cardiac “funny current” (If) is among the cAMP-sensitive effectors that drive pacemaking in SAMs. If is produced by hyperpolarization-activated, cyclic nucleotide-sensitive (HCN) channels. Voltage-dependent gating of HCN channels is potentiated by cAMP, which acts either by binding directly to the channels or by activating the cAMP-dependent protein kinase (PKA), which phosphorylates them. PKA activity is required for signaling between β adrenergic receptors (βARs) and HCN channels in SAMs but the mechanism that constrains cAMP signaling to a PKA-dependent pathway is unknown. Phosphodiesterases (PDEs) hydrolyze cAMP and form cAMP signaling domains in other types of cardiomyocytes. Here we examine the role of PDEs in regulation of If in SAMs. If was recorded in whole-cell voltage-clamp experiments from acutely-isolated mouse SAMs in the absence or presence of PDE and PKA inhibitors, and before and after βAR stimulation. General PDE inhibition caused a PKA-independent depolarizing shift in the midpoint activation voltage (V1/2) of If at rest and removed the requirement for PKA in βAR-to-HCN signaling. PDE4 inhibition produced a similar PKA-independent depolarizing shift in the V1/2 of If at rest, but did not remove the requirement for PKA in βAR-to-HCN signaling. PDE3 inhibition produced PKA-dependent changes in If both at rest and in response to βAR stimulation. Our results suggest that PDE3 and PDE4 isoforms create distinct cAMP signaling domains that differentially constrain access of cAMP to HCN channels and establish the requirement for PKA in signaling between βARs and HCN channels in SAMs.

Molecular Basis of Altered hERG1 Channel Gating Induced by Ginsenoside Rg3.

Outward current conducted by human ether-à-go-go-related gene type 1 (hERG1) channels is a major determinant of action potential repolarization in the human ventricle. Ginsenoside 20(S)-Rg3 [Rg3; (2S,3R,4S,5S,6R)-2-[(2R,3R,4S,5S,6R)-4,5-dihydroxy-2-[[(3S,5R,8R,9R,10R,12R,13R,14R,17S)-12-hydroxy-17-[(2S)-2-hydroxy-6-methylhept-5-en-2-yl]-4,4,8,10,14-pentamethyl-2,3,5,6,7,9,11,12,13,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]-6-(hydroxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol], an alkaloid isolated from the root of Panax ginseng, slows the rate of hERG1 deactivation, induces channels to open at more negative potentials than normal, and increases current magnitude. The onset of Rg3 action is extremely fast, suggesting that it binds to an extracellular accessible site on the channel to alter its gating. Here we used a scanning mutagenesis approach to identify residues in the extracellular loops and transmembrane segments of hERG1 that might interact with Rg3. Single or multiple residues of hERG1 were mutated to Ala or Cys and the resulting mutant channels were heterologously expressed in Xenopus oocytes. The effects of Rg3 on the voltage dependence of activation and the deactivation rate of mutant channel currents were characterized using the two-microelectrode voltage clamp technique. Mutation to Ala of specific residues in the S1 (Tyr420), S2 (Leu452, Phe463), and S4 (Ile521, Lys525) segments partially inhibited the effects of Rg3 on hERG1. The double mutant Y420A/L452A nearly eliminated the effects of Rg3 on voltage-dependent channel gating but did not prevent the increase in current magnitude. These findings together with molecular modeling suggest that Rg3 alters the gating of hERG1 channels by interacting with and stabilizing the voltage sensor domain in an activated state.