Channel Conductance Research Articles

Direct Current Stimulation Modulates Synaptic Facilitation via Distinct Presynaptic Calcium Channels

Transcranial direct current stimulation (tDCS) is a subthreshold neurostimulation technique known for ameliorating neuropsychiatric conditions. The principal mechanism of tDCS is the differential polarization of subcellular neuronal compartments, particularly the axon terminals that are sensitive to external electrical fields. Yet, the underlying mechanism of tDCS is not fully clear. Here, we hypothesized that direct current stimulation (DCS)-induced modulation of presynaptic calcium channel conductance alters axon terminal dynamics with regard to synaptic vesicle release. To examine the involvement of calcium-channel subtypes in tDCS, we recorded spontaneous excitatory postsynaptic currents (sEPSCs) from cortical layer-V pyramidal neurons under DCS while selectively inhibiting distinct subtypes of voltage-dependent calcium channels. Blocking P/Q or N-type calcium channels occluded the effects of DCS on sEPSCs, demonstrating their critical role in the process of DCS-induced modulation of spontaneous vesicle release. However, inhibiting T-type calcium channels did not occlude DCS-induced modulation of sEPSCs, suggesting that despite being active in the subthreshold range, T-type calcium channels are not involved in the axonal effects of DCS. DCS modulates synaptic facilitation by regulating calcium channels in axon terminals, primarily via controlling P/Q and N-type calcium channels, while T-type calcium channels are not involved in this mechanism.

Nanowire-Enhanced Fully Transparent and Flexible Indium Gallium Zinc Oxide Transistors with Chitosan Hydrogel Gate Dielectric: A Pathway to Improved Synaptic Properties.

In this study, a transparent and flexible synaptic transistor was fabricated based on a random-network nanowire (NW) channel made of indium gallium zinc oxide. This device employs a biocompatible chitosan-based hydrogel as an electrolytic gate dielectric. The NW structure, with its high surface-to-volume ratio, facilitated a more effective modulation of the channel conductance induced by protonic-ion polarization. A comparative analysis of the synaptic properties of NW- and film-type devices revealed the distinctive features of the NW-type configuration. In particular, the NW-type synaptic transistors exhibited a significantly larger hysteresis window under identical gate-bias conditions. Notably, these transistors demonstrated enhanced paired-pulse facilitation properties, synaptic weight modulation, and transition from short- to long-term memory. The NW-type devices displayed gradual potentiation and depression of the channel conductance and thus achieved a broader dynamic range, improved linearity, and reduced power consumption compared with their film-type counterparts. Remarkably, the NW-type synaptic transistors exhibited impressive recognition accuracy outcomes in Modified National Institute of Standards and Technology pattern-recognition simulations. This characteristic enhances the efficiency of practical artificial intelligence (AI) processes. Consequently, the proposed NW-type synaptic transistor is expected to emerge as a superior candidate for use in high-efficiency artificial neural network systems, thus making it a promising technology for next-generation AI semiconductor applications.

Mechanistic basis of ligand efficacy in the calcium-activated chloride channel TMEM16A.

Agonist binding in ligand-gated ion channels is coupled to structural rearrangements around the binding site, followed by the opening of the channel pore. In this process, agonist efficacy describes the equilibrium between open and closed conformations in a fully ligand-bound state. Calcium-activated chloride channels in the TMEM16 family are important sensors of intracellular calcium signals and are targets for pharmacological modulators, yet a mechanistic understanding of agonist efficacy has remained elusive. Using a combination of cryo-electron microscopy, electrophysiology, and autocorrelation analysis, we now show that agonist efficacy in the ligand-gated channel TMEM16A is dictated by the conformation of the pore-lining helix α6 around the Ca2+ -binding site. The closure of the binding site, which involves the formation of a π-helix below a hinge region in α6, appears to be coupled to the opening of the inner pore gate, thereby governing the channel's open probability and conductance. Our results provide a mechanism for agonist binding and efficacy and a structural basis for the design of potentiators and partial agonists in the TMEM16 family.

Controllable magnetic anisotropy and conductivity in ScCrSe3 monolayer driven by electrostatic doping

Above-room-temperature intrinsic ferromagnetism and superior transport property are critical for low-dimensional spintronic devices. Here, some main features of the ScCrSe3 monolayer and their changes under electrostatic doping are unveiled by means of the first-principles calculations and Monte Carlo simulations. The ScCrSe3 monolayer displays a feature of room-temperature ferromagnetic semiconductor with a Curie temperature of 350 K and an indirect bandgap of 2.13 eV. The magnetic anisotropy energy is 0.115 meV per unit cell. The Curie temperature above room-temperature increases with hole doping. The physical mechanism by which the easy magnetization axis of the ScCrSe3 monolayer undergoes a transition from in-plane to out-of-plane direction at a doping concentration of 0.2 holes per unit cell is discussed in detail. Moreover, the conductivity of spin-up and spin-down channels can be enhanced significantly under hole doping. Our results suggest that ScCrSe3 monolayer is a promising two-dimensional room-temperature ferromagnetic material with potential applications in low-dimensional spintronics.

Wavelength-Controlled Photoconductance Polarity Switching via Harnessing Defects in Doped PdSe2 for Artificial Synaptic Features.

Optoelectronic synapses are currently drawing significant attention as fundamental building blocks of neuromorphic computing to mimic brain functions. In this study, a two-terminal synaptic device based on a doped PdSe2 flake is proposed to imitate the key neural functions in an optical pathway. Due to the wavelength-dependent desorption of oxygen clusters near the intrinsic selenide vacancy defects, the doped PdSe2 photodetector achieves a high negative photoresponsivity of -7.8 × 103 A W-1 at 473nm and a positive photoresponsivity of 181 A W-1 at 1064nm. This wavelength-selective bi-direction photoresponse endows an all-optical pathway to imitate the fundamental functions of artificial synapses on a device level, such as psychological learning and forgetting capability, as well as dynamic logic functions. The underpinning photoresponse is further demonstrated on a flexible platform, providing a viable technology for neuromorphic computing in wearable electronics. Furthermore, the p-type doping results in an effective increase of the channel's electrical conductivity and a significant reduction in power consumption. Such low-power-consuming optical synapses with simple device architecture and low-dimensional features demonstrate tremendous promise for building multifunctional artificial neuromorphic systems in the future.

A spin field effect transistor based on a strained two dimensional layer of a Weyl semimetal

Spin field effect transistors (SpinFET) are an iconic class of spintronic transistor devices that exploit gate tuned spin-orbit interaction in semiconductor channels interposed between ferromagnetic source and drain contacts to elicit transistor functionality. Recently, a new and different type of SpinFET based on gate tuned strain in quantum materials (e.g. topological insulators) has been proposed and may have interesting analog applications, such as in frequency multiplication, by virtue of its unusual oscillatory transfer characteristic. Here, we propose and analyze yet another type of SpinFET in this class, which may have a different application. It is based on gate-tuned strain in a Weyl semimetal, with the strain modulating spin interference. Because the operating principle is non-classical, the channel conductance shows oscillatory dependence on the channel length at zero gate voltage. Furthermore, the transconductance can switch sign if the channel length is varied. This latter feature can be exploited to implement a complementary device like complementary metal oxide semiconductor (CMOS) by connecting two such SpinFETs of slightly different channel lengths in series. These unusual properties may have niche applications.

Interface-type tunable oxygen ion dynamics for physical reservoir computing

Reservoir computing can more efficiently be used to solve time-dependent tasks than conventional feedforward network owing to various advantages, such as easy training and low hardware overhead. Physical reservoirs that contain intrinsic nonlinear dynamic processes could serve as next-generation dynamic computing systems. High-efficiency reservoir systems require nonlinear and dynamic responses to distinguish time-series input data. Herein, an interface-type dynamic transistor gated by an Hf0.5Zr0.5O2 (HZO) film was introduced to perform reservoir computing. The channel conductance of Mott material La0.67Sr0.33MnO3 (LSMO) can effectively be modulated by taking advantage of the unique coupled property of the polarization process and oxygen migration in hafnium-based ferroelectrics. The large positive value of the oxygen vacancy formation energy and negative value of the oxygen affinity energy resulted in the spontaneous migration of accumulated oxygen ions in the HZO films to the channel, leading to the dynamic relaxation process. The modulation of the channel conductance was found to be closely related to the current state, identified as the origin of the nonlinear response. In the time series recognition and prediction tasks, the proposed reservoir system showed an extremely low decision-making error. This work provides a promising pathway for exploiting dynamic ion systems for high-performance neural network devices.

Electrophoresis of ions and electrolyte conductivity: From bulk to nanochannels.

When electrolyte solutions are confined in micro- and nanochannels their conductivity is significantly different from those in a bulk phase. Here we revisit the theory of this phenomenon by focusing attention on the reduction in the ion mobility with the concentration of salt and a consequent impact to the conductivity of a monovalent solution, from bulk to confined in a narrow slit. We first give a systematic treatment of electrophoresis of ions and obtain equations for their zeta potentials and mobilities. The latter are then used to obtain a simple expression for a bulk conductivity, which is valid in a concentration range up to a few molars and more accurate than prior analytic theories. By extending the formalism to the electrolyte solution in the charged channel the equations describing the conductivity in different modes are presented. They can be regarded as a generalization of prior work on the channel conductivity to a more realistic case of a nonzero reduction of the electrophoretic mobility of ions with salt concentration. Our analysis provides a framework for interpreting measurements on the conductivity of electrolyte solutions in the bulk and in narrow channels.

Power efficient MoS2 synaptic devices based on Maxwell–Wagner interfacial charging in binary oxides

Synaptic devices with tunable weight hold great promise in enabling non-von Neumann architecture for energy efficient computing. However, conventional metal-insulator-metal based two-terminal memristors share the same physical channel for both programming and reading, therefore the programming power consumption is dependent on the synaptic resistance states and can be particularly high when the memristor is in the low resistance states. Three terminal synaptic transistors, on the other hand, allow synchronous programming and reading and have been shown to possess excellent reliability. Here we present a binary oxide based three-terminal MoS2 synaptic device, in which the channel conductance can be modulated by interfacial charges generated at the oxide interface driven by Maxwell-Wagner instability. The binary oxide stack serves both as an interfacial charge host and gate dielectrics. Both excitatory and inhibitory behaviors are experimentally realized, and the presynaptic potential polarity can be effectively controlled by engineering the oxide stacking sequence, which is a unique feature compared with existing charge-trap based synaptic devices and provides a new tuning knob for controlling synaptic device characteristics. By adopting a three-terminal transistor structure, the programming channel and reading channel are physically separated and the programming power consumption can be kept constantly low (∼50 pW) across a wide dynamic range of 105. This work demonstrates a complementary metal oxide semiconductor compatible approach to build power efficient synaptic devices for artificial intelligence applications.

Capsazepine activates amiloride-insensitive ENaC-like channels in human leukemia cells

Sodium influx carried out by ion channels is one of the main regulators of water-salt and volume balance in cells of blood origin. Previously, we described amiloride-insensitive ENaC-like channels in human myeloid leukemia K562 cells; the intracellular regulatory mechanisms of the channels are associated with actin cytoskeleton dynamics. Recently, an extracellular mechanism of ENaC-like channels activation in K562 cells by the action of serine protease trypsin has been revealed. The other extracellular pathways that modulate ENaC (epithelial Na+ channel) activity and sodium permeability in transformed blood cells are not yet fully investigated. Here, we study the action of capsazepine (CPZ), as δ-ENaC activator, on single channel activity in K562 cells in whole-cell patch clamp experiments. Addition of CPZ (2 μM) to the extracellular solution caused an activation of sodium channels with typical features; unitary conductance was 15.1 ± 0.8 pS. Amiloride derivative benzamil (50 μM) did not inhibit their activity. Unitary currents and conductance of CPZ-activated channels were higher in Na+-containing extracellular solution than in Li+, that is one of the main fingerprints of δ-ENaC. The results of RT-PCR analysis and immunofluorescence staining also confirmed the expression of δ-hENaC (as well as α-, β-, γ-ENaC) at the mRNA and protein level. These findings allow us to speculate that CPZ activates amiloride-insensitive ENaC-like channels that contain δ-ENaC in К562 cells. Our data reveal a novel extracellular mechanism for ENaC-like activation in human leukemia cells.

Drill-In Fluid Optimization for Formation Damage Control Considering Salt Dissolution in Saline-Lacustrine Reservoirs

Summary Salt dissolution induced by drill-in fluid loss is a frequent occurrence in saline-lacustrine reservoirs, which can potentially result in serious formation damage. In light of this, an experimental study was conducted to investigate the salt mineral dissolution and dynamic damage in the rock samples collected from a saline-lacustrine carbonate reservoir and the response of pore-fracture structures using the in-situ drill-in fluids. The study further involved analyzing the formation-damage-control (FDC) ability of the in-situ drill-in fluids. The results indicated that although salt dissolution significantly increased the pore size of the tight matrix and the width of natural fractures, improving the conductivity of seepage channels, the increase in pore-fracture size may have greatly aggravated the drill-in fluid loss during the process. The continuous serious filtrate loss, lower pressure-bearing capacity of the plugging zone, and lower permeability recovery rate (PRR) of rock indicated poor FDC performance of in-situ brine drilling fluids for the salt-dissolved core samples. The FDC performance of drill-in fluids for saline-lacustrine carbonate reservoirs was optimized based on the response of reservoir pore-fracture structure to salt dissolution and the theory of slightly underbalanced activity. The experimental results showed that the optimized drill-in fluids had better FDC ability, with an average PRR increase of 14.04%. Field application indicated that the optimized drill-in fluids reduced the drill-in fluid loss by 76.48%, shortened the drilling cycle by 45.20%, and increased the initial production capacity per well by 7.70%. This study can provide insightful guidance to optimize the FDC performance of drill-in fluids for saline-lacustrine hydrocarbon reservoirs during drilling.

Laterally gated ferroelectric field effect transistor (LG-FeFET) using α-In2Se3 for stacked in-memory computing array

In-memory computing is an attractive alternative for handling data-intensive tasks as it employs parallel processing without the need for data transfer. Nevertheless, it necessitates a high-density memory array to effectively manage large data volumes. Here, we present a stacked ferroelectric memory array comprised of laterally gated ferroelectric field-effect transistors (LG-FeFETs). The interlocking effect of the α-In2Se3 is utilized to regulate the channel conductance. Our study examined the distinctive characteristics of the LG-FeFET, such as a notably wide memory window, effective ferroelectric switching, long retention time (over 3 × 104 seconds), and high endurance (over 105 cycles). This device is also well-suited for implementing vertically stacked structures because decreasing its height can help mitigate the challenges associated with the integration process. We devised a 3D stacked structure using the LG-FeFET and verified its feasibility by performing multiply-accumulate (MAC) operations in a two-tier stacked memory configuration.

Advancements in Complementary Metal-Oxide Semiconductor-Compatible Tunnel Barrier Engineered Charge-Trapping Synaptic Transistors for Bio-Inspired Neural Networks in Harsh Environments.

This study aimed to propose a silicon-on-insulator (SOI)-based charge-trapping synaptic transistor with engineered tunnel barriers using high-k dielectrics for artificial synapse electronics capable of operating at high temperatures. The transistor employed sequential electron trapping and de-trapping in the charge storage medium, facilitating gradual modulation of the silicon channel conductance. The engineered tunnel barrier structure (SiO2/Si3N4/SiO2), coupled with the high-k charge-trapping layer of HfO2 and high-k blocking layer of Al2O3, enabled reliable long-term potentiation/depression behaviors within a short gate stimulus time (100 μs), even under elevated temperatures (75 and 125 °C). Conductance variability was determined by the number of gate stimuli reflected in the maximum excitatory postsynaptic current (EPSC) and the residual EPSC ratio. Moreover, we analyzed the Arrhenius relationship between the EPSC as a function of the gate pulse number (N = 1-100) and the measured temperatures (25, 75, and 125 °C), allowing us to deduce the charge trap activation energy. A learning simulation was performed to assess the pattern recognition capabilities of the neuromorphic computing system using the modified National Institute of Standards and Technology datasheets. This study demonstrates high-reliability silicon channel conductance modulation and proposes in-memory computing capabilities for artificial neural networks using SOI-based charge-trapping synaptic transistors.

Short-Term Amyloid Beta Application Decreased Glutamate Release, but Increased Glutamate Spillover in Hippocampal Neurons

Aim: Synaptic dysfunction is a characteristic linked with the early stages of Alzheimer's disease (AD), but the pathological mechanisms remain elusive. It was aimed to investigate how amyloid beta 42 (Abeta42) peptide affects miniature events mediated by glutamate release in hippocampal neurons.
 Material and Methods: We performed all experiments in the primary cultured hippocampal neurons in control and Abeta42-treated neurons (24 h). Pharmacologically isolated miniature excitatory postsynaptic currents (mEPSCs) were obtained in whole-cell voltage-clamp configuration at – 70 mV. AMPAergic channel conductance and basic synaptic parameters were evaluated by performing peak-scaled variance analysis and cumulative event analysis and glutamate spillover is determined by application of DNQX.
 Results: The oligomeric Abeta42 for 24h decreased the mEPSCs frequency (***p

Bor arsenit bazlı nano-transistörlerde elektrotların enerji aralığı üzerindeki genişlik etkisinin incelenmesi, bir DFT çalışması

This study deals with electronic properties of Boron Arsenide nanoribbons using Density function theory (DFT) calculations. Under specific conditions, nanoribbons can be used as Nano-transistors. It is feasible to modify nanoribbons' electronic properties, such as bandgap and conductivity, by varying their width and edge shape. Source, drain, and gate are basic parts of a conventional field-effect transistor (FET). The channel's conductivity can be changed by applying a voltage to the gate electrode. In current research, boron Arsenide nanoribbons has been investigated as lead electrode of a transistor and stability of the sheet has been confirmed by positive phonon vibrational modes. Utilizing the band structure spectrum, band gap as an electronic property is measured and reported. Different width values for electrodes have been considered and it has represented that the band gap is size dependent and increasing in ribbon’s size to bulk structure, results in decrements in band gap energy value.

Modulation Doping of Silicon Nanowires to Tune the Contact Properties of Nano‐Scale Schottky Barriers

AbstractDoping silicon on the nanoscale by the intentional introduction of impurities into the intrinsic semiconductor suffers from effects such as dopant deactivation, random dopant fluctuations, out‐diffusion, and mobility degradation. This paper presents the first experimental proof that doping of silicon nanowires can also be achieved via the purposeful addition of aluminium‐induced acceptor states to the SiO2 shell around a silicon nanowire channel. It is shown that modulation doping lowers the overall resistance of silicon nanowires with nickel silicide Schottky contacts by up to six orders of magnitude. The effect is consistently observed for various channel geometries and systematically studied as a function of Al2O3 content during fabrication. The transfer length method is used to separate the effects on the channel conductivity from that on the barriers. A silicon resistivity is achieved as low as 0.04–0.06 Ω ·cm in the nominal undoped material. In addition, the specific contact resistivity is also strongly influenced by the modulation doping and reduced down to 3.5E‐7 Ω · cm2, which relates to lowering the effective Schottky barrier to 0.09 eV. This alternative doping method has the potential to overcome the issues associated with doping and contact formation on the nanoscale.

Supramolecular Barrel‐Rosette Ion Channel Based on 3,5‐Diaminobenzoic Acid for Cation‐Anion Symport

AbstractThe structural tropology and functions of natural cation‐anion symporting channels have been continuously investigated due to their crucial role in regulating various physiological functions. To understand the physiological functions of the natural symporter channels, it is vital to develop small‐molecule‐based biomimicking systems that can provide mechanistic insights into the ion‐binding sites and the ion‐translocation pathways. Herein, we report a series of bis((R)‐(−)‐mandelic acid)‐linked 3,5‐diaminobenzoic acid based self‐assembled ion channels with distinctive ion transport ability. Ion transport experiment across the lipid bilayer membrane revealed that compound 1 b exhibits the highest transport activity among the series, and it has interesting selective co‐transporting functions, i.e., facilitates K+/ClO4− symport. Electrophysiology experiments confirmed the formation of supramolecular ion channels with an average diameter of 6.2±1 Å and single channel conductance of 57.3±1.9 pS. Selectivity studies of channel 1 b in a bilayer lipid membrane demonstrated a permeability ratio of , , and indicating the higher selectivity of the channel towards KClO4 over KCl salt. A hexameric assembly of a trimeric rosette of 1 b was subjected to molecular dynamics simulations with different salts to understand the supramolecular channel formation and ion selectivity pattern.

Supramolecular Barrel-Rosette Ion Channel Based on 3,5-Diaminobenzoic Acid for Cation-Anion Symport.

The structural tropology and functions of natural cation-anion symporting channels have been continuously investigated due to their crucial role in regulating various physiological functions. To understand the physiological functions of the natural symporter channels, it is vital to develop small molecule-based biomimicking systems that can provide mechanistic insights into the ion-binding sites and the ion-translocation pathways. Herein, we report a series of bis((R)-(-)-mandelic acid)-linked 3,5-diaminobenzoic acid-based self-assembled ion channels with distinctive ion transport ability. Ion transport experiment across the lipid bilayer membrane revealed that compound 1b exhibits the highest transport activity among the series, and it has interesting selective co-transporting functions, i.e., facilitates K+/ClO4- symport. Electrophysiology experiments confirmed the formation of supramolecular ion channels with an average diameter of 6.2 ± 1 Å and single channel conductance of 57.3 ± 1.9 pS. Selectivity studies of channel 1b in BLM demonstrated the permeability ratio of PCl-/PK+ = 0.053 ±0.02, PClO4-/PCl- = 2.1 ± 0.5, and PK+/PNa+ = 1.5 ± 1, respectively, indicating the higher selectivity of the channel towards KClO4 over KCl salt. A hexameric assembly of a trimeric rosette of 1b was subjected to molecular dynamics simulations with different salts to understand the supramolecular channel formation and ion selectivity pattern.

Dopamine-Regulated Plasticity in MoO3 Synaptic Transistors.

Field-effect transistor-based biosensors have gained increasing interest due to their reactive surface to external stimuli and the adaptive feedback required for advanced sensing platforms in biohybrid neural interfaces. However, complex probing methods for surface functionalization remain a challenge that limits the industrial implementation of such devices. Herein, a simple, label-free biosensor based on molybdenum oxide (MoO3) with dopamine-regulated plasticity is demonstrated. Dopamine oxidation facilitated locally at the channel surface initiates a charge transfer mechanism between the molecule and the oxide, altering the channel conductance and successfully emulating the tunable synaptic weight by neurotransmitter activity. The oxygen level of the channel is shown to heavily affect the device's electrochemical properties, shifting from a nonreactive metallic characteristic to highly responsive semiconducting behavior. Controllable responsivity is achieved by optimizing the channel's dimension, which allows the devices to operate in wide ranges of dopamine concentration, from 100 nM to sub-mM levels, with excellent selectivity compared with K+, Na+, and Ca2+.

Genetic Inhibition of APOL1 Pore-Forming Function Prevents APOL1-Mediated Kidney Disease.

African Americans are at increased risk of CKD in part due to high-risk (HR) variants in the apolipoprotein L1 ( APOL1 ) gene, termed G1/G2. A different APOL1 variant, p.N264K , reduced the risk of CKD and ESKD among carriers of APOL1 HR variants to levels comparable with individuals with APOL1 low-risk variants in an analysis of 121,492 participants of African ancestry from the Million Veteran Program (MVP). Functional genetic studies in cell models showed that APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR mutations. Pharmacologic inhibitors that mimic this mutation blocking APOL1 -mediated pore formation may be able to prevent and/or treat APOL1 -associated kidney disease. African Americans are at increased risk for nondiabetic CKD in part due to HR variants in the APOL1 gene. We tested whether a different APOL1 variant, p.N264K , modified the association between APOL1 HR genotypes (two copies of G1/G2) and CKD in a cross-sectional analysis of 121,492 participants of African ancestry from the MVP. We replicated our findings in the Vanderbilt University Biobank ( n =14,386) and National Institutes of Health All of Us ( n =14,704). Primary outcome was CKD and secondary outcome was ESKD among nondiabetic patients. Primary analysis compared APOL1 HR genotypes with and without p.N264K . Secondary analyses included APOL1 low-risk genotypes and tested for interaction. In MVP, we performed sequential logistic regression models adjusting for demographics, comorbidities, medications, and ten principal components of ancestry. Functional genomic studies expressed APOL1 HR variants with and without APOL1 p.N264K in cell models. In the MVP cohort, 15,604 (12.8%) had two APOL1 HR variants, of which 582 (0.5%) also had APOL1 p.N264K . In MVP, 18,831 (15%) had CKD, 4177 (3%) had ESKD, and 34% had diabetes. MVP APOL1 HR, without p.N264K , was associated with increased odds of CKD (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.60 to 1.85) and ESKD (OR, 3.94; 95% CI, 3.52 to 4.41). In MVP, APOL1 p.N264K mitigated the renal risk of APOL1 HR, in CKD (OR, 0.43; 95% CI, 0.28 to 0.65) and ESKD (OR, 0.19; CI 0.07 to 0.51). In the replication cohorts meta-analysis, APOL1 p.N264K mitigated the renal risk of APOL1 HR in CKD (OR, 0.40; 95% CI, 0.18 to 0.92) and ESKD (OR, 0.19; 95% CI, 0.05 to 0.79). In the mechanistic studies, APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR variants. APOL1 p.N264K is associated with reduced risk of CKD and ESKD among carriers of APOL1 HR to levels comparable with individuals with APOL1 low-risk genotypes.