scholarly journals Gating mechanism of human N-type voltage-gated calcium channel

2021 ◽  
Author(s):  
Yanli Dong ◽  
Yiwei Gao ◽  
Shuai Xu ◽  
Yuhang Wang ◽  
Zhuoya Yu ◽  
...  
Keyword(s):  
Resting State ◽  
Complex Structure ◽  
The Other ◽  
Nociceptive Transmission ◽  
Voltage Gated ◽  
Gating Mechanisms ◽  
Cryo Electron Microscopy ◽  
Gating Mechanism ◽  
Voltage Sensing Domain ◽  
Structural Insights

N-type voltage-gated calcium (CaV) channels mediate Ca2+ influx at the presynaptic terminals in response to action potential and play vital roles in synaptogenesis, neurotransmitter releasing, and nociceptive transmission. Here we elucidate a cryo-electron microscopy (cryo-EM) structure of the human CaV2.2 complex at resolution of 2.8 Å. This complex structure reveals how the CaV2.2, β1, and α2δ1 subunits are assembled. In our structure, the second voltage-sensing domain (VSD) is stabilized at a resting-state conformation, which is distinct from the other three VSDs of CaV2.2 as well as activated VSDs observed in previous structures of CaV channels. The structure also shows that the intracellular gate formed by S6 helices is closed, and a W-helix from the DII-III linker is determined to act as a blocking-ball that causes closed-state inactivation in CaV2.2. Collectively, our structure provides previously unseen structural insights into fundamental gating mechanisms of CaV channels.

scholarly journals Resting-State Structure and Gating Mechanism of a Voltage-Gated Sodium Channel

Cell ◽  
2019 ◽  
Vol 178 (4) ◽  
pp. 993-1003.e12 ◽  
Author(s):  
Goragot Wisedchaisri ◽  
Lige Tonggu ◽  
Eedann McCord ◽  
Tamer M. Gamal El-Din ◽  
Liguo Wang ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Resting State ◽  
State Structure ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Gating Mechanism

scholarly journals Resting state structure of the hyperdepolarization activated two-pore channel 3

2020 ◽  
Vol 117 (4) ◽  
pp. 1988-1993
Author(s):  
Miles Sasha Dickinson ◽  
Alexander Myasnikov ◽  
Jacob Eriksen ◽  
Nicole Poweleit ◽  
Robert M. Stroud
Keyword(s):  
Resting State ◽  
Action Potentials ◽  
Pore Channel ◽  
Activation Threshold ◽  
Voltage Gated ◽  
Bona Fide ◽  
Voltage Gated Ion Channels ◽  
Voltage Sensing Domain ◽  
Voltage Activation ◽  
Closed Pore

Voltage-gated ion channels endow membranes with excitability and the means to propagate action potentials that form the basis of all neuronal signaling. We determined the structure of a voltage-gated sodium channel, two-pore channel 3 (TPC3), which generates ultralong action potentials. TPC3 is distinguished by activation only at extreme membrane depolarization (V50 ∼ +75 mV), in contrast to other TPCs and NaV channels that activate between −20 and 0 mV. We present electrophysiological evidence that TPC3 voltage activation depends only on voltage sensing domain 2 (VSD2) and that each of the three gating arginines in VSD2 reduces the activation threshold. The structure presents a chemical basis for sodium selectivity, and a constricted gate suggests a closed pore consistent with extreme voltage dependence. The structure, confirmed by our electrophysiology, illustrates the configuration of a bona fide resting state voltage sensor, observed without the need for any inhibitory ligand, and independent of any chemical or mutagenic alteration.

Voltage-gating and cytosolic Ca2+ activation mechanisms of Arabidopsis two-pore channel AtTPC1

2021 ◽  
Vol 118 (49) ◽  
pp. e2113946118
Author(s):  
Fan Ye ◽  
Lingyi Xu ◽  
Xiaoxiao Li ◽  
Weizhong Zeng ◽  
Ninghai Gan ◽  
...  
Keyword(s):  
Voltage Gating ◽  
Pore Channel ◽  
Voltage Gated ◽  
Gating Mechanism ◽  
Ef Hand ◽  
Activation Mechanisms ◽  
Voltage Gated Ion Channels ◽  
Structural Mechanisms ◽  
Voltage Sensing Domain ◽  
Insight Into

Arabidopsis thaliana two-pore channel AtTPC1 is a voltage-gated, Ca2+-modulated, nonselective cation channel that is localized in the vacuolar membrane and responsible for generating slow vacuolar (SV) current. Under depolarizing membrane potential, cytosolic Ca2+ activates AtTPC1 by binding at the EF-hand domain, whereas luminal Ca2+ inhibits the channel by stabilizing the voltage-sensing domain II (VSDII) in the resting state. Here, we present 2.8 to 3.3 Å cryoelectron microscopy (cryo-EM) structures of AtTPC1 in two conformations, one in closed conformation with unbound EF-hand domain and resting VSDII and the other in a partially open conformation with Ca2+-bound EF-hand domain and activated VSDII. Structural comparison between the two different conformations allows us to elucidate the structural mechanisms of voltage gating, cytosolic Ca2+ activation, and their coupling in AtTPC1. This study also provides structural insight into the general voltage-gating mechanism among voltage-gated ion channels.

Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins

Science ◽  
2019 ◽  
Vol 363 (6433) ◽  
pp. 1303-1308 ◽  
Author(s):  
Huaizong Shen ◽  
Dongliang Liu ◽  
Kun Wu ◽  
Jianlin Lei ◽  
Nieng Yan
Keyword(s):  
Electron Microscopy ◽  
Pain Relief ◽  
Sodium Channel ◽  
Voltage Gated Sodium Channel ◽  
Auxiliary Subunits ◽  
Voltage Gated ◽  
Cryo Electron Microscopy ◽  
Promising Target ◽  
Gating Modifier ◽  
Voltage Sensing Domain

Voltage-gated sodium channel Nav1.7 represents a promising target for pain relief. Here we report the cryo–electron microscopy structures of the human Nav1.7-β1-β2 complex bound to two combinations of pore blockers and gating modifier toxins (GMTs), tetrodotoxin with protoxin-II and saxitoxin with huwentoxin-IV, both determined at overall resolutions of 3.2 angstroms. The two structures are nearly identical except for minor shifts of voltage-sensing domain II (VSDII), whose S3-S4 linker accommodates the two GMTs in a similar manner. One additional protoxin-II sits on top of the S3-S4 linker in VSDIV. The structures may represent an inactivated state with all four VSDs “up” and the intracellular gate closed. The structures illuminate the path toward mechanistic understanding of the function and disease of Nav1.7 and establish the foundation for structure-aided development of analgesics.

Computer processing of high-resolution images of periodic specimens

1986 ◽  
Vol 44 ◽  
pp. 2-5
Author(s):  
W. Chiu ◽  
M.F. Schmid ◽  
T.-W. Jeng
Keyword(s):  
High Resolution ◽  
Fourier Transforms ◽  
Complex Structure ◽  
Distribution Functions ◽  
Multiple Image ◽  
Cryo Electron Microscopy ◽  
Structure Factors ◽  
Unit Cells ◽  
High Resolution Images ◽  
Phase Probability Distribution

Cryo-electron microscopy has been developed to the point where one can image thin protein crystals to 3.5 Å resolution. In our study of the crotoxin complex crystal, we can confirm this structural resolution from optical diffractograms of the low dose images. To retrieve high resolution phases from images, we have to include as many unit cells as possible in order to detect the weak signals in the Fourier transforms of the image. Hayward and Stroud proposed to superimpose multiple image areas by combining phase probability distribution functions for each reflection. The reliability of their phase determination was evaluated in terms of a crystallographic “figure of merit”. Grant and co-workers used a different procedure to enhance the signals from multiple image areas by vector summation of the complex structure factors in reciprocal space.

scholarly journals Structure of the full-length human Pannexin1 channel and insights into its role in pyroptosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Sensen Zhang ◽  
Baolei Yuan ◽  
Jordy Homing Lam ◽  
Jun Zhou ◽  
Xuan Zhou ◽  
...  
Keyword(s):  
Md Simulation ◽  
Potential Role ◽  
Md Simulations ◽  
Full Length ◽  
Inflammasome Activation ◽  
Simulation Studies ◽  
Cryo Electron Microscopy ◽  
Gating Mechanism ◽  
Atp Efflux

AbstractPannexin1 (PANX1) is a large-pore ATP efflux channel with a broad distribution, which allows the exchange of molecules and ions smaller than 1 kDa between the cytoplasm and extracellular space. In this study, we show that in human macrophages PANX1 expression is upregulated by diverse stimuli that promote pyroptosis, which is reminiscent of the previously reported lipopolysaccharide-induced upregulation of PANX1 during inflammasome activation. To further elucidate the function of PANX1, we propose the full-length human Pannexin1 (hPANX1) model through cryo-electron microscopy (cryo-EM) and molecular dynamics (MD) simulation studies, establishing hPANX1 as a homo-heptamer and revealing that both the N-termini and C-termini protrude deeply into the channel pore funnel. MD simulations also elucidate key energetic features governing the channel that lay a foundation to understand the channel gating mechanism. Structural analyses, functional characterizations, and computational studies support the current hPANX1-MD model, suggesting the potential role of hPANX1 in pyroptosis during immune responses.

scholarly journals A Study of the Effects of Rain, Snow and Hail on the Atmospheric Electric Field near Ground

Atmosphere ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 996
Author(s):  
Athanasios Karagioras ◽  
Konstantinos Kourtidis
Keyword(s):  
Frequency Distribution ◽  
Complex Structure ◽  
Potential Gradient ◽  
Weather Conditions ◽  
The Other ◽  
Fair Weather ◽  
Northern Greece ◽  
Rain Events ◽  
The Impact ◽  
Bounce Back

The purpose of the present study is to investigate the impact of rain, snow and hail on potential gradient (PG), as observed in a period of ten years in Xanthi, northern Greece. An anticorrelation between PG and rainfall was observed for rain events that lasted several hours. When the precipitation rate was up to 2 mm/h, the decrease in PG was between 200 and 1300 V/m, in most cases being around 500 V/m. An event with rainfall rates up to 11 mm/h produced the largest drop in PG, of 2 kV/m. Shortly after rain, PG appeared to bounce back to somewhat higher values than the ones of fair-weather conditions. A decrease in mean hourly PG was observed, which was around 2–4 kV/m during the hail events which occurred concurrently with rain and from 0 to 3.5 kV/m for hail events with no rain. In the case of no drop, no concurrent drop in temperature was observed, while, for the other cases, it appeared that, for each degree drop in temperature, the drop in hourly mean PG was 1000 V/m; hence, we assume that the intensity of the hail event regulates the drop in PG. The frequency distribution of 1-minute PG exhibits a complex structure during hail events and extend from −18 to 11 kV/m, with most of the values in the negative range. During snow events, 1-minute PG exhibited rapid fluctuations between high positive and high negative values, its frequency distribution extending from −10 to 18 kV/m, with peaks at −10 and 3 kV/m.

scholarly journals A Converging Consensus of the Structure of a Voltage-Sensing Domain in its Resting State

2011 ◽  
Vol 100 (3) ◽  
pp. 367a
Author(s):  
Ernesto Vargas ◽  
Francisco Bezanilla ◽  
Benoit Roux
Keyword(s):  
Resting State ◽  
Voltage Sensing ◽  
Voltage Sensing Domain

Ion-channel gating mechanisms: model identification and parameter estimation from single channel recordings

1989 ◽  
Vol 236 (1285) ◽  
pp. 385-416 ◽  
Keyword(s):  
Parameter Estimation ◽  
Single Channel ◽  
Channel Gating ◽  
Model Identification ◽  
Simulated Data ◽  
Process Models ◽  
Gating Mechanisms ◽  
Gating Mechanism ◽  
Incorrect Model ◽  
Schwarz Criterion

Patch-clamp data may be analysed in terms of Markov process models of channel gating mechanisms. We present a maximum likelihood algorithm for estimation of gating parameters from records where only a single channel is present. Computer simulated data for three different models of agonist receptor gated channels are used to demonstrate the performance of the procedure. Full details of the implementation of the algorithm are given for an example gating mechanism. The effects of omission of brief openings and closings from the single-channel data on parameter estimation are explored. A strategy for discriminating between alternative possible gating models, based upon use of the Schwarz criterion, is described. Omission of brief events is shown not to lead to incorrect model identification, except in extreme circumstances. Finally, the algorithm is extended to include channel gating models exhibiting multiple conductance levels.

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