15 results on '"gating model"'
Search Results
2. Gating mechanism of the human α1β GlyR by glycine.
- Author
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Liu, Xiaofen and Wang, Weiwei
- Subjects
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NEUROTRANSMITTER receptors , *GLYCINE , *BINDING sites , *MATHEMATICAL models , *ELECTROPHYSIOLOGY - Abstract
Glycine receptors (GlyRs) are members of the Cys-loop receptors that constitute a major portion of mammalian neurotransmitter receptors. Recent resolution of heteromeric GlyR structures in multiple functional states raised fundamental questions regarding the gating mechanism of GlyR, and generally the Cys-loop family receptors. Here, we characterized in detail equilibrium properties as well as the transition kinetics between functional states. We show that, while all allosteric sites bind cooperatively to glycine, occupation of 2 sites at the α-α interfaces is sufficient for activation and necessary for high-efficacy gating. Differential glycine concentration dependence of desensitization rate, extent, and its recovery suggests separate but concerted roles of ligand-binding and ionophore reorganization. Based on these observations and available structural information, we developed a quantitative gating model that accurately predicts both equilibrium and kinetical properties throughout the glycine gating cycle. This model likely applies generally to the Cys-loop receptors and informs on pharmaceutical endeavors. [Display omitted] • Glycine binding at 2 α1-α1 allosteric sites is sufficient and necessary for gating • Desensitization is dominated by intrinsic properties of the TM instead of ECD • Glycine dissociation underlies steady-state desensitization extent and its recovery • Quantitative model recapitulating complete gating cycle Liu et al. characterized the steady-state and kinetic properties of human heteromeric GlyR throughout the gating cycle. Through strategically generated mutations, basic gating properties were identified, which led to a mathematical gating model. This quantitative model hints on the fundamental principles underlying heteromeric Cys-loop receptor family function. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
3. Local multiple kernel extreme learning machine fault diagnosis model with dynamic fuzzy clustering for avionics.
- Author
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DAI Jinling and XU Aiqiang
- Subjects
FAULT diagnosis ,MACHINE learning ,AVIONICS ,DYNAMIC models ,FUZZY algorithms ,FALSE alarms - Abstract
To improve the module-level fault diagnosis rate for avionics in a small sample size, based on the adaptive feature of dynamic fuzzy clustering and the local feature of local multiple kernel learning (LMKL), a local multiple kernel extreme learning machine (LMKELM) model for avionics is proposed. The model confirms the number of clusters adaptively by introducing the concept of local density. Local density is combined with the fuzzy C-means algorithm to realize dynamic fuzzy clustering, which well reflects the diversity between clusters and reduces calculation. A gating model is constructed to solve the non-convex quadratic problem of local weight. Fault diagnosis of test samples is realized by fusing information of local weight and membership. The proposed model is applied into a certain type of rotary transformer excitation generating circuit. Compared with the four fashionable multiple kernel learning methods, the proposed model performs better in terms of false alarm and missing alarm rate. The experimental result shows that the applied M
1 and M2 gating models enhance the average accuracy by 2.78% and 4.37% respectively. [ABSTRACT FROM AUTHOR]- Published
- 2021
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4. Multiple Matrix Learning Machine with Five Aspects of Pattern Information.
- Author
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Zhu, Changming and Gao, Daqi
- Subjects
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MACHINE learning , *PATTERN perception , *COMPUTATIONAL complexity , *COMPARATIVE studies , *CLUSTER analysis (Statistics) - Abstract
This paper proposes an effective Multiple Matrix Learning Machine with Five Aspects of Pattern Information (MMFI). First aspect lies in the class label of each training or validation pattern. Second aspect is the values of components for each pattern. Third aspect is the relationship between patterns in the local regions of input space. Fourth aspect is the representation information and discriminant roles of different matrix representations for patterns. Fifth aspect is the information of patterns in each matrix representation learning. The innovations of the proposed MMFI are: (1) establishing a pattern-dependent function in the matrix learning so as to realize different roles of patterns for the first time; (2) adopting five aspects of pattern information so that a more feasible learning machine can be trained. The advantages of MMFI are: (1) proposing a new nonlinear learning machine which is different from the state-of-the-art kernelization one; (2) achieving a statistically superior classification performance than those learning machines without the introduction of five aspects of pattern information; (3) possessing a lower or comparable computational-complexity than other compared multiple matrix learning machines. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
5. Multiple empirical kernel learning based on local information.
- Author
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Wang, Zhe, Xu, Jin, Gao, Daqi, and Fu, Yu
- Subjects
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KERNEL (Mathematics) , *MACHINE learning , *PATTERN recognition systems , *GATING system (Founding) , *BENCHMARK problems (Computer science) , *MATHEMATICAL mappings , *ARTIFICIAL neural networks - Abstract
The traditional multiple kernel learning (MKL) is usually based on implicit kernel mapping and adopts a certain combination of kernels instead of a single kernel. MKL has been demonstrated to have a significant advantage to the single-kernel learning. Although MKL sets different weights to different kernels, the weights are not changed over the whole input space. This weight setting might not been fit for those data with some underlying local distributions. In order to solve this problem, Gönen and Alpaydın ( 2008 ) introduced a localizing gating model into the traditional MKL framework so as to assign different weights to a kernel in different regions of the input space. In this paper, we also integrate the localizing gating model into our previous work named MultiK-MHKS that is an effective multiple empirical kernel learning. In doing so, we can get multiple localized empirical kernel learning named MLEKL. Our contribution is that we first establish a localized formulation in the empirical kernel learning framework. The experimental results on benchmark data sets validate the effectiveness of the proposed MLEKL. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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6. Double-fold localized multiple matrixized learning machine.
- Author
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Zhu, Changming, Wang, Zhe, Gao, Daqi, and Feng, Xiang
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MATRICES (Mathematics) , *MACHINE learning , *EMPIRICAL research , *DISCRIMINANT analysis , *CLASSIFICATION - Abstract
In this paper, we develop an effective multiple-matrixized learning machine named Double-fold Localized Multiple Matrixized Learning Machine (DLMMLM). The characteristic of the proposed DLMMLM is that it possesses double folds of local information from data. The first fold lies in the whole representation space which consists of different matrix representations. It is known that each pattern can be represented by different matrix representations. The matrices have their respective representation information and can play different discriminant roles in the final classification. Therefore from the viewpoint of the whole representation space, each matrix has its own local information. The second fold is that in each matrix representation learning, different patterns represented with the same matrix representation can carry different information. Therefore in the pattern space with the same matrix size, local information of different patterns should be introduced into the classifier design. On the whole, the advantages of the proposed DLMMLM are: (i) establishing a pattern-depended function in the matrixized learning so as to realize different roles of patterns for the first time; (ii) adopting the double-fold local information in both the representation space and the pattern space; (iii) proposing a new nonlinear classifier that is different from the state-of-the-art kernelization one; and (iv) getting a tighter empirical generalization risk bound in terms of the Rademacher complexity and thus achieving a statistically superior classification performance than those classifiers without the introduction of the double-fold local information. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
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7. Gating of the HypoPP-1 mutations: II. Effects of a calcium-channel agonist BayK 8644.
- Author
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Kuzmenkin, Alexey, Chao Hang, Kuzmenkina, Elza, and Jurkat-Rott, Karin
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HYPOKALEMIA , *CALCIUM channels , *RABBITS , *ANIMAL models in research , *MUTAGENESIS , *IONIC structure , *DIAGNOSIS - Abstract
L-type calcium-channel mutations causing hypokalemic periodic paralysis type 1 (HypoPP-1) have pronounced “loss-of-function” features and stabilize the less-selective second open state O2, as we demonstrated in the companion paper. Here, we compared the effects of the L-type calcium-channel activator (±)BayK 8644 (BayK) on the heterologously expressed wild-type (WT) calcium channel, rabbit Cav1.2 HypoPP-1 analogs, and two double mutants (R650H/R1362H, R650H/R1362G). Our goal was to elucidate (1) whether the “loss-of-function” in HypoPP-1 can be compensated by BayK application, (2) how the less-selective open state is affected by BayK in WT and HypoPP-1 mutants, as well as (3) to gain an insight into BayK mechanism of action. Ionic currents were examined by whole-cell patch-clamp and analyzed by the global-fitting procedure. Our results imply that (1) BayK promotes channel activation, but equalized the differences among the WT and mutants, thus attenuating HypoPP-related effects on activation and deactivation; (2) BayK binds to the first open state O1, and then serves as a catalyst for O2 formation; (3) binding of BayK is impaired in the HypoPP mutants, thus affecting the formation of the less-selective second open state; (4) BayK affects cooperativity between the single HypoPP-1 mutations at all stages of the channel gating; and (5) BayK favoring of O2 lowers calcium-channel selectivity. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
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8. Gating of the HypoPP-1 mutations: I. Mutant-specific effects and cooperativity.
- Author
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Kuzmenkin, Alexey, Chao Hang, Kuzmenkina, Elza, and Jurkat-Rott, Karin
- Subjects
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HYPOKALEMIA , *PARALYSIS , *ACTIVE biological transport , *CALCIUM channels , *GENETIC mutation , *GENETICS - Abstract
Hypokalemic periodic paralysis type 1 (HypoPP-1) is a hereditary muscular disorder caused by point mutations in the gene encoding the voltage-gated Ca2+ channel α subunit (Cav1.1). Despite extensive research, the results on HypoPP-1 mutations are minor and controversial, as it is difficult to analyse Ca2+ channel activation macroscopically due to an existence of two open states. In this study, we heterologously expressed the wild-type and HypoPP-1 mutations introduced into the rabbit cardiac Ca2+ channel (R650H, R1362H, R1362G) in HEK-293 cells. To examine the cooperative effects of the mutations on channel gating, we expressed two double mutants (R650H/R1362H, R650H/R1362G). We performed whole-cell patch-clamp and, to obtain more information, applied a global fitting procedure whereby several current traces elicited by different potentials were simultaneously fit to the kinetic model containing four closed, two open and two inactivated states. We found that all HypoPP-1 mutations have “loss-of-function” features: D4/S4 mutations shift the equilibrium to the closed states, which results in reduced open probability, shorter openings and, therefore, in smaller currents, and the D2/S4 mutant slows the activation. In addition, HypoPP-1 histidine mutants favored the second open state O2 with a possibly lower channel selectivity. Cooperativity between the D2/S4 and D4/S4 HypoPP-1 mutations manifested in dominant effects of the D4/S4 mutations on kinetics of the double mutants, suggesting different roles of D2/S4 and D4/S4 voltage sensors in the gating of voltage-gated calcium channels. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
9. Evidence for common structural determinants of activation and inactivation in T-type Ca2+ channels.
- Author
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Talavera, Karel and Nilius, Bernd
- Subjects
- *
CALCIUM channels , *MOSAICISM , *GENE transfection , *GENETIC polymorphisms , *CELL proliferation , *CELL differentiation - Abstract
One of the most distinctive features of T-type Ca2+ channels is their fast inactivation. Recent structure–function studies indicate that the rate of macroscopic inactivation of these channels is influenced by several structural components, including intracellular linkers, transmembrane segments, and pore loops. The macroscopic inactivation of T-type channels is partially coupled to activation. It is therefore possible that changes in the rate of macroscopic inactivation after alteration in the structure of these channels might actually result from changes in activation kinetics. In this study, we use kinetic simulations to illustrate how the alteration of the rate of channel activation may lead to changes in the rate of macroscopic inactivation. By examining data pooled from several structure–function studies we demonstrate that gating modifications induced by alteration in the channel structure unveils a correlation between the time constants of macroscopic inactivation and activation. This analysis underscores the relevance of considering the inactivation–activation coupling when analyzing the structural determinants of T-type channel inactivation. Furthermore, we demonstrate that slow-inactivating mutants, with modifications in the IIIS6 segment and the proximal C terminus, display significant alterations in the voltage dependencies of activation and deactivation with respect to the wild type channel CaV3.1. Our results indicate that common structures, most likely the S6 transmembrane segments, are involved in the conformational changes occurring during both channel activation and inactivation. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
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10. Three types of membrane excitations in the marine diatom Coscinodiscus wailesii.
- Author
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Gradmann, D. and Boyd, C.M.
- Subjects
BIOLOGICAL membranes ,CELL membranes ,OSMOREGULATION ,WATER-electrolyte balance (Physiology) ,OSMOSIS ,CHARACEAE ,ALGAE physiology ,ACTION potentials ,CELLULAR signal transduction ,COMPARATIVE studies ,COMPUTER simulation ,CYTOLOGY ,BIOLOGICAL evolution ,RESEARCH methodology ,MEDICAL cooperation ,MEMBRANE proteins ,RESEARCH ,EVALUATION research ,OSMOTIC pressure - Abstract
Three types of electrical excitation have been investigated in the marine diatom Coscinodiscus wailesii. I: Depolarization-triggered, transient Cl(-) conductance, G(Cl)(t), followed by a transient, voltage-gated K(+) conductance, G(K), with an active state a and two inactive states i(1) and i(2) in series (a-i(1)-i(2)). II: Similar G(Cl)(t) as in Type-I but triggered by hyperpolarization; a subsequent increase of G(K) in this type is indicated but not analyzed in detail. III: Hyperpolarization-induced transient of a voltage-gated activity of an electrogenic pump (i(2)-a-i(2)), followed by G(Cl)(t) as in Type-II excitations. Type-III with pump gating is novel as such. G(Cl)(t) in all types seems to reflect the mechanism of InsP(-)(3) and Ca(2+)-mediated G(Cl)(t) in the action potential in Chara (Biskup et al., 1999). The nonlinear current-voltage-time relationships of Type-I and Type-III excitations have been recorded under voltage-clamp using single saw-tooth command voltages (voltage range: -200 to +50 mV, typical slope: +/-1 Vs(-1)). Fits of the corresponding models to the experimental data provided numerical values of the model parameters. The statistical significance of these solutions is investigated. We suggest that the original function of electrical excitability of biological membranes is related to osmoregulation which has persisted through evolution in plants, whereas the familiar and osmotically neutral action potentials in animals have evolved later towards the novel function of rapid transmission of information over long distances. [ABSTRACT FROM AUTHOR]
- Published
- 2000
- Full Text
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11. Stabilization of a channel’s open state by a hydrophobic residue in the sixth membrane-spanning segment (S6) of rKv1.4.
- Author
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Zhou, Ying-Ying, Jiang, M., Ling, Shiun, and Tseng, G.-N.
- Abstract
We report the effects of mutating a threonine residue at position 529 (T529) in the middle of the S6 segment of rKv1.4 on the voltage-dependence and kinetics of activation and deactivation. Replacing T529 with glycine (no side chain) or with a residue that has a hydrophobic side chain (T529L, T529I, T529V, T529A, or T529F) caused a slowing of deactivation, along with a negative shift in the activation curve and a voltage-dependent slowing of activation. Numerical simulation showed that these effects could be reproduced by decreasing the rate constant for a transition from open to closed states. The degree of slowing of deactivation largely correlated with the degree of increase in 529 side-chain hydrophobicity. Specifically, the 529 mutation-induced alteration in free energy change accompanying deactivation per channel could be accounted for by the increase in free energy needed to transfer the 529 side chain of one subunit from a hydrophobic environment to an aqueous environment. We propose that in the open state, the 529 side chain faces a hydrophobic protein interior. The rate-limiting step in channel deactivation includes a conformational change in one subunit’s S6 segment, moving its 529 side chain to face the aqueous lumen of the pore. [ABSTRACT FROM AUTHOR]
- Published
- 1998
- Full Text
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12. Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin.
- Author
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Xu, Hui, Li, Tianbo, Rohou, Alexis, Arthur, Christopher P., Tzakoniati, Foteini, Wong, Evera, Estevez, Alberto, Kugel, Christine, Franke, Yvonne, Chen, Jun, Ciferri, Claudio, Hackos, David H., Koth, Christopher M., and Payandeh, Jian
- Subjects
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VOLTAGE-gated ion channels , *SODIUM channels , *CYSTINE , *PEPTIDES , *X-ray crystallography - Abstract
Summary Voltage-gated sodium (Nav) channels are targets of disease mutations, toxins, and therapeutic drugs. Despite recent advances, the structural basis of voltage sensing, electromechanical coupling, and toxin modulation remains ill-defined. Protoxin-II (ProTx2) from the Peruvian green velvet tarantula is an inhibitor cystine-knot peptide and selective antagonist of the human Nav1.7 channel. Here, we visualize ProTx2 in complex with voltage-sensor domain II (VSD2) from Nav1.7 using X-ray crystallography and cryoelectron microscopy. Membrane partitioning orients ProTx2 for unfettered access to VSD2, where ProTx2 interrogates distinct features of the Nav1.7 receptor site. ProTx2 positions two basic residues into the extracellular vestibule to antagonize S4 gating-charge movement through an electrostatic mechanism. ProTx2 has trapped activated and deactivated states of VSD2, revealing a remarkable ∼10 Å translation of the S4 helix, providing a structural framework for activation gating in voltage-gated ion channels. Finally, our results deliver key templates to design selective Nav channel antagonists. Graphical Abstract Highlights Spider toxin ProTx2 engages the Nav1.7 channel through a membrane access pathway The toxin uses an electrostatic mechanism to oppose voltage sensor domain II activation The toxin complexes with activated and deactivated states of voltage sensor domain II A basis for electromechanical coupling in voltage-gated ion channels is revealed Seeing how a spider toxin blocks a sodium channel suggests a structural basis for channel gating and avenues for developing new modulators. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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13. イオンチャンネルのゲート機構解析モデル
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open probability ,dwell-time histogram ,gating model ,ion channel ,%22">intracellular Ca^<2+> - Published
- 2004
14. Evidence for common structural determinants of activation and inactivation in T-type Ca2+ channels
- Author
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Talavera, Karel and Nilius, Bernd
- Published
- 2006
- Full Text
- View/download PDF
15. Rapid Activation of the Cardiac Ryanodine Receptor by Submillisecond Calcium Stimuli
- Author
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Sandor Gyorke, Alexandra Zahradníková, Ivan Zahradník, and Inna Györke
- Subjects
Patch-Clamp Techniques ,cardiac muscle ,Physiology ,Lipid Bilayers ,Gating ,Acetates ,In Vitro Techniques ,calcium signaling ,010402 general chemistry ,Models, Biological ,01 natural sciences ,03 medical and health sciences ,Dogs ,Microsomes ,ryanodine receptor ,Animals ,Patch clamp ,Lipid bilayer ,Chelating Agents ,030304 developmental biology ,Calcium signaling ,0303 health sciences ,Photolysis ,gating model ,Chemistry ,Ryanodine receptor ,Myocardium ,Endoplasmic reticulum ,Time constant ,Heart ,Ryanodine Receptor Calcium Release Channel ,musculoskeletal system ,Ethylenediamines ,sarcoplasmic reticulum ,0104 chemical sciences ,Coupling (electronics) ,Kinetics ,Biochemistry ,Biophysics ,Calcium ,Original Article ,tissues ,Ion Channel Gating ,Algorithms - Abstract
The local control concept of excitation–contraction coupling in the heart postulates that the activity of the sarcoplasmic reticulum ryanodine receptor channels (RyR) is controlled by Ca2+entry through adjoining sarcolemmal single dihydropyridine receptor channels (DHPRs). One unverified premise of this hypothesis is that the RyR must be fast enough to track the brief (2+elevations accompanying single DHPR channel openings. To define the kinetic limits of effective trigger Ca2+signals, we recorded activity of single cardiac RyRs in lipid bilayers during rapid and transient increases in Ca2+generated by flash photolysis of DM-nitrophen. Application of such Ca2+spikes (amplitude ∼10–30 μM, duration ∼0.1–0.4 ms) resulted in activation of the RyRs with a probability that increased steeply (apparent Hill slope ∼2.5) with spike amplitude. The time constants of RyR activation were 0.07–0.27 ms, decreasing with spike amplitude. To fit the rising portion of the open probability, a single exponential function had to be raised to a powern∼ 3. We show that these data could be adequately described with a gating scheme incorporating four sequential Ca2+-sensitive closed states between the resting and the first open states. These results provide evidence that brief Ca2+triggers are adequate to activate the RyR, and support the possibility that RyR channels are governed by single DHPR openings. They also provide evidence for the assumption that RyR activation requires binding of multiple Ca2+ions in accordance with the tetrameric organization of the channel protein.
- Published
- 1999
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