scholarly journals Voltage-gated channels formed in lipid bilayers by a positively charged segment of the Na-channel polypeptide.

1989 ◽  
Vol 86 (2) ◽  
pp. 707-710 ◽  
Author(s):  
M. T. Tosteson ◽  
D. S. Auld ◽  
D. C. Tosteson
Keyword(s):  
Lipid Bilayers ◽  
Na Channel ◽  
Voltage Gated ◽  
Voltage Gated Channels ◽  
Positively Charged

scholarly journals Changes in Local S4 Environment Provide a Voltage-sensing Mechanism for Mammalian Hyperpolarization–activated HCN Channels

2003 ◽  
Vol 123 (1) ◽  
pp. 5-20 ◽  
Author(s):  
Damian C. Bell ◽  
Huan Yao ◽  
Renee C. Saenger ◽  
John H. Riley ◽  
Steven A. Siegelbaum
Keyword(s):  
Hcn Channels ◽  
Transmembrane Segment ◽  
Voltage Sensing ◽  
Voltage Gated ◽  
Transmembrane Segments ◽  
Pacemaker Channels ◽  
Gated Channel ◽  
Voltage Gated Channels ◽  
S4 Segment ◽  
Positively Charged

The positively charged S4 transmembrane segment of voltage-gated channels is thought to function as the voltage sensor by moving charge through the membrane electric field in response to depolarization. Here we studied S4 movements in the mammalian HCN pacemaker channels. Unlike most voltage-gated channel family members that are activated by depolarization, HCN channels are activated by hyperpolarization. We determined the reactivity of the charged sulfhydryl-modifying reagent, MTSET, with substituted cysteine (Cys) residues along the HCN1 S4 segment. Using an HCN1 channel engineered to be MTS resistant except for the chosen S4 Cys substitution, we determined the reactivity of 12 S4 residues to external or internal MTSET application in either the closed or open state of the channel. Cys substitutions in the NH2-terminal half of S4 only reacted with external MTSET; the rates of reactivity were rapid, regardless of whether the channel was open or closed. In contrast, Cys substitutions in the COOH-terminal half of S4 selectively reacted with internal MTSET when the channel was open. In the open state, the boundary between externally and internally accessible residues was remarkably narrow (∼3 residues). This suggests that S4 lies in a water-filled gating canal with a very narrow barrier between the external and internal solutions, similar to depolarization-gated channels. However, the pattern of reactivity is incompatible with either classical gating models, which postulate a large translational or rotational movement of S4 within a gating canal, or with a recent model in which S4 forms a peripheral voltage-sensing paddle (with S3b) that moves within the lipid bilayer (the KvAP model). Rather, we suggest that voltage sensing is due to a rearrangement in transmembrane segments surrounding S4, leading to a collapse of an internal gating canal upon channel closure that alters the shape of the membrane field around a relatively static S4 segment.

scholarly journals Statistical Approach to Incorporating Experimental Variability into a Mathematical Model of the Voltage-Gated Na+ Channel and Human Atrial Action Potential

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1516
Author(s):  
Daniel Gratz ◽  
Alexander J Winkle ◽  
Seth H Weinberg ◽  
Thomas J Hund
Keyword(s):  
Action Potential ◽  
Mathematical Models ◽  
Cardiac Myocyte ◽  
Population Level ◽  
Na Channel ◽  
Model Parameters ◽  
Healthy Population ◽  
Experimental Measurements ◽  
Voltage Gated ◽  
Experimental Variability

The voltage-gated Na+ channel Nav1.5 is critical for normal cardiac myocyte excitability. Mathematical models have been widely used to study Nav1.5 function and link to a range of cardiac arrhythmias. There is growing appreciation for the importance of incorporating physiological heterogeneity observed even in a healthy population into mathematical models of the cardiac action potential. Here, we apply methods from Bayesian statistics to capture the variability in experimental measurements on human atrial Nav1.5 across experimental protocols and labs. This variability was used to define a physiological distribution for model parameters in a novel model formulation of Nav1.5, which was then incorporated into an existing human atrial action potential model. Model validation was performed by comparing the simulated distribution of action potential upstroke velocity measurements to experimental measurements from several different sources. Going forward, we hope to apply this approach to other major atrial ion channels to create a comprehensive model of the human atrial AP. We anticipate that such a model will be useful for understanding excitability at the population level, including variable drug response and penetrance of variants linked to inherited cardiac arrhythmia syndromes.

Block of Human Heart hH1 Sodium Channels by the Enantiomers of Bupivacaine

2000 ◽  
Vol 93 (4) ◽  
pp. 1022-1033 ◽  
Author(s):  
Carla Nau ◽  
Sho-Ya Wang ◽  
Gary R. Strichartz ◽  
Ging Kuo Wang
Keyword(s):  
Human Heart ◽  
Point Mutations ◽  
Cell Voltage ◽  
Site Directed Mutagenesis ◽  
Na Channel ◽  
Amino Acid Residues ◽  
Na Channels ◽  
State Dependent ◽  
Positively Charged

Background S(-)-bupivacaine reportedly exhibits lower cardiotoxicity but similar local anesthetic potency compared with R(+)-bupivacaine. The bupivacaine binding site in human heart (hH1) Na+ channels has not been studied to date. The authors investigated the interaction of bupivacaine enantiomers with hH1 Na+ channels, assessed the contribution of putatively relevant residues to binding, and compared the intrinsic affinities to another isoform, the rat skeletal muscle (mu1) Na+ channel. Methods Human heart and mu1 Na+ channel alpha subunits were transiently expressed in HEK293t cells and investigated during whole cell voltage-clamp conditions. Using site-directed mutagenesis, the authors created point mutations at positions hH1-F1760, hH1-N1765, hH1-Y1767, and hH1-N406 by introducing the positively charged lysine (K) or the negatively charged aspartic acid (D) and studied their influence on state-dependent block by bupivacaine enantiomers. Results Inactivated hH1 Na+ channels displayed a weak stereoselectivity with a stereopotency ratio (+/-) of 1.5. In mutations hH1-F1760K and hH1-N1765K, bupivacaine affinity of inactivated channels was reduced by approximately 20- to 40-fold, in mutation hH1-N406K by approximately sevenfold, and in mutations hH1-Y1767K and hH1-Y1767D by approximately twofold to threefold. Changes in recovery of inactivated mutant channels from block paralleled those of inactivated channel affinity. Inactivated hH1 Na+ channels exhibited a slightly higher intrinsic affinity than mu1 Na+ channels. Conclusions Differences in bupivacaine stereoselectivity and intrinsic affinity between hH1 and mu1 Na+ channels are small and most likely of minor clinical relevance. Amino acid residues in positions hH1-F1760, hH1-N1765, and hH1-N406 may contribute to binding of bupivacaine enantiomers in hH1 Na+ channels, whereas the role of hH1-Y1767 remains unclear.

scholarly journals Double mutant gating perturbation analysis predicts a high conformational stability of the domain IV S6 segment of the voltage-gated Na+ channel

2009 ◽  
Vol 9 (Suppl 2) ◽  
pp. A25
Author(s):  
René Cervenka ◽  
Touran Zarrabi ◽  
Péter Lukács ◽  
Xaver König ◽  
Karlheinz Hilber ◽  
...  
Keyword(s):  
Perturbation Analysis ◽  
Double Mutant ◽  
Conformational Stability ◽  
Na Channel ◽  
Voltage Gated

scholarly journals Ca 2+ /Calmodulin-Dependent Protein Kinase II–Based Regulation of Voltage-Gated Na + Channel in Cardiac Disease

Circulation ◽  
2012 ◽  
Vol 126 (17) ◽  
pp. 2084-2094 ◽  
Author(s):  
Olha M. Koval ◽  
Jedidiah S. Snyder ◽  
Roseanne M. Wolf ◽  
Ryan E. Pavlovicz ◽  
Patric Glynn ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cardiac Disease ◽  
Na Channel ◽  
Dependent Protein Kinase ◽  
Voltage Gated ◽  
Protein Kinase Ii ◽  
Dependent Protein

Simulation on the Physical Process of Neural Electromagnetic Signal Generation Based on a Simple but Functional Bionic Na+ Channel

2021 ◽  
Author(s):  
Fan Wang ◽  
Jingjing Xu ◽  
Yanbin Ge ◽  
Shengyong Xu ◽  
Yanjun Fu ◽  
...  
Keyword(s):  
Dynamic Equilibrium ◽  
Electromagnetic Signal ◽  
Na Channel ◽  
Physical Processes ◽  
Flux Transport ◽  
Ionic Flux ◽  
Concentration Difference ◽  
Voltage Gated ◽  
Electromagnetic Signals ◽  
The Impact

Abstract The physical processes occurring at open Na+ channels in neural fibers are essential for understanding the nature of neural signals and the mechanism by which the signals are generated and transmitted along nerves. However, there is less generally accepted description of these physical processes. We studied changes in the transmembrane ionic flux and the resulting two types of electromagnetic signals by simulating the Na+ transport across a bionic nanochannel model simplified from voltage-gated Na+ channels. Results show that the Na+ flux can reach a steady state in approximately 10 ns owing to the dynamic equilibrium of Na+ ions concentration difference between the both sides of membrane. After characterizing the spectrum and transmission of these two electromagnetic signals, the low-frequency transmembrane electric field is regarded as the physical quantity transmitting in waveguide-like lipid dielectric layer and triggering the neighboring voltage-gated channels. Factors influencing the Na+ flux transport are also studied. The impact of the Na+ concentration gradient is found higher than that of the initial transmembrane potential on the Na+ transport rate, and introducing the surface-negative charge in the upper third channel could increase the transmembrane Na+ current. This work can be further studied by improving the simulation model; however, the current work helps to better understand the electrical functions of voltage-gated ion channels in neural systems.

scholarly journals Polysaccharides from Portulaca oleracea L. regulated insulin secretion in INS-1 cells through voltage-gated Na channel

2019 ◽  
Vol 109 ◽  
pp. 876-885 ◽  
Author(s):  
Qingjuan Hu ◽  
Qingchuan Niu ◽  
Hao Song ◽  
Shanshan Wei ◽  
Songhua Wang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Portulaca Oleracea ◽  
Na Channel ◽  
Voltage Gated
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