Electromechanics of lipid-modulated gating of potassium channels

2021 ◽  
pp. 108128652110600
Author(s):  
Nidhin Thomas ◽  
Kranthi K Mandadapu ◽  
Ashutosh Agrawal
Keyword(s):  
Electrostatic Interactions ◽  
Experimental Studies ◽  
Vertical Motion ◽  
Cationic Lipid ◽  
Anionic Lipid ◽  
Electromechanical Model ◽  
Kv Channels ◽  
Model Predictions ◽  
Pore Domain ◽  
Voltage Sensor Domain

Experimental studies reveal that the anionic lipid phosphatidic acid (POPA), non-phospholipid cholesterol, and cationic lipid DOTAP inhibit the gating of voltage-sensitive potassium (Kv) channels. Here, we develop a continuum electromechanical model to investigate the interaction of these lipids with the ion channel. Our model suggests that: (i) POPA lipids may restrict the vertical motion of the voltage-sensor domain through direct electrostatic interactions; (ii) cholesterol may oppose the radial motion of the pore domain of the channel by increasing the mechanical rigidity of the membrane; and (iii) DOTAP can reduce the effect of electrostatic forces by regulating the dielectric constant at the channel–lipid interface. The electromechanical model predictions for the three lipid types match well with the experimental observations and provide mechanistic insights into lipid-dependent gating of Kv channels.

scholarly journals Electromechanics of lipid-modulated gating of Kv channels

2020 ◽  
Author(s):  
Nidhin Thomas ◽  
Kranthi K. Mandadapu ◽  
Ashutosh Agrawal
Keyword(s):  
Electrostatic Interactions ◽  
Experimental Studies ◽  
Vertical Motion ◽  
Voltage Sensor ◽  
Atomistic Simulations ◽  
Head Group ◽  
Minimal Impact ◽  
Electromechanical Model ◽  
Kv Channels ◽  
Lipid Environment

Experimental studies reveal that anionic lipid POPA and non-phospholipid cholesterol inhibit the gating of voltage-sensitive potassium (Kv) channels at 5–10% molar concentrations. Intriguingly, other anionic lipids similar to POPA, like POPG, have minimal impact on the gating of the same channels for reasons that remain obscure. Our long-timescale atomistic simulations show that POPA preferentially solvates the voltage sensor domains of Kv channels by direct electrostatic interactions between the positively charged arginine and negatively charged phosphate groups. Cholesterol solvates the voltage sensor domains through CH-π interactions between the cholesterol rings and the aromatic side chains of phenylalanine and tyrosine residues. A continuum electromechanical model predicts that POPA lipids may restrict the vertical motion of voltage-sensor domain through direct electrostatic interactions, while cholesterol may oppose the radial motion of the pore domain of the channel by increasing the mechanical rigidity of the membrane. The electromechanical model predictions are consistent with measurements of the activation curves of Kv channels for various lipids. The atomistic simulations also suggest that the solvation due to POPG is much weaker likely due to its bigger head-group size. Thus the channel activity appears to be tied to the local lipid environment, allowing lipids to regulate channel gating in low concentrations.

Ball Grid Array Thermomechanical Response During Reflow Assembly

1996 ◽  
Vol 118 (4) ◽  
pp. 214-222 ◽  
Author(s):  
T. E. Voth ◽  
T. L. Bergman
Keyword(s):  
Process Model ◽  
Experimental Studies ◽  
Ball Grid Array ◽  
Mechanical Processing ◽  
Processing Conditions ◽  
System Behavior ◽  
Reflow Soldering ◽  
Thermomechanical Response ◽  
Model Predictions ◽  
Representative System

The thermomechanical response of ball-grid array assemblies during reflow soldering is considered here. Experiments are performed to investigate the thermomechanical response of a representative system and the results are used to validate a numerical model of system behavior. The conclusions drawn from the experimental studies are used to guide development of a process model capable of describing more realistic BGA soldering scenarios. Process model predictions illustrate the system’s thermomechanical response to thermal and mechanical processing conditions, as well as component properties. High thermal conductivity assemblies show the greatest sensitivity to mechanical loading conditions.

Experimental Studies on Attenuation of Rotor-Stator Dynamics: Effects of High-Frequency Inclusion and Annular Fluid

2018 ◽  
Author(s):  
Meryem Kanzari ◽  
Mohammed AlQaradawi ◽  
Balakumar Balachandran
Keyword(s):  
High Frequency ◽  
Complex Dynamics ◽  
Experimental Studies ◽  
Flexible Rotor ◽  
Flexible Rotors ◽  
Speed Modulation ◽  
Model Predictions ◽  
Drive Speed ◽  
The Stability ◽  
Three Degree Of Freedom

Flexible, rotating structures can experience complex dynamics, when torsional and lateral motions are involved. Oilwell drill strings form one example of such structures. In the present study, the authors investigate the influence of sinusoidal drive speed modulation on whirling motions of flexible rotors with contact interactions. For two types of drilling-like operations, one with drill mud and another without drill mud, the stability of motions is studied. A laboratory-scale drill rig is used to study the dynamics of a flexible rotor, which is driven at one end and housed within a stator at the other end. Experimental results are presented and discussed for different drive speeds. The findings suggest that the addition of drill mud in the annular space between the rotor and stator along with high-frequency modulation in the drive input helps attenuate lateral motions. The torsional motions appear to be influenced more by the high-frequency drive speed modulation. A three-degree-of-freedom model has been constructed to study lateraltorsional dynamics of a rotor-stator system. The model predictions are compared with the experimental data. The findings of this work have relevance for constructing practical solutions to control whirl dynamics of flexible rotors such as drill strings.

scholarly journals Residues Connecting Voltage Sensor Domain to Pore Domain in Shaker K+ Channel by Noncanonical Coupling Mechanism

2020 ◽  
Vol 118 (3) ◽  
pp. 333a
Author(s):  
Carlos Alberto Z. Bassetto Jr ◽  
Joao L. Carvalho-de-Souza ◽  
Francisco Bezanilla
Keyword(s):  
Voltage Sensor ◽  
K Channel ◽  
Coupling Mechanism ◽  
Pore Domain ◽  
Voltage Sensor Domain

Dynamic Processes in Vacuum Contact Devices of Robots for Vertical Motion in the Water Environment

2019 ◽  
Vol 20 (7) ◽  
pp. 417-421
Author(s):  
V. G. Gradetsky ◽  
M. M. Knyazkov ◽  
E. A. Semenov ◽  
A. N. Sukhanov
Keyword(s):  
Nuclear Power ◽  
Power Plants ◽  
Water Environment ◽  
Experimental Studies ◽  
Vertical Motion ◽  
Contact Device ◽  
Dynamic Processes ◽  
Simplified Models ◽  
Contact Devices ◽  
Air Ejector

The results of experimental investigation intended to improve movement conditions for pneumatic robots on vertical surfaces under water are discussed. Features of the movement of vacuum contact devices for the simulation of mathematical model of the vacuum contact device with surfaces under water are presented. The experimental studies made it possible to obtain additional data on the dynamics of attachment, to obtain transient processes for air-water flow through ejector and to correct the results obtained earlier. For the purpose of analytical study of dynamic processes occurring in the system of vacuum contact devices, and taking into account the complexity of the description of nonlinearities, linearized simplified models of the system "air ejector — contact device — water environment" were developed. Vacuum contact devices are designed to provide guaranteed contact with vertical surfaces, plane slopes or horizontal surfaces on which the underwater robot performs its movement, carrying out the prescribed technological tasks, for example, in dry wells of nuclear power plants, on the surfaces of ship hulls, on the surfaces of underwater structures. The models took into account the forces of adhesion to the surfaces under water — the forces from the pressure drop, the friction force, the contact and vacuum interaction, the elasticity of suction caps. As a result of the solution of the model problem, the values of mechanical parameters, as well as the values of vacuum and flow in the cavity of variable volume as functions of changing the gap between the end of the corrugated membrane and the surfaces are obtained explicitly. As a result of the study of dynamic processes occurring in simplified models of vacuum contact devices "air ejector — contact surface — water environment", the transient characteristics of the change in the operating forces and pressures over time, as well as the dependence of the normal and tangential components of the forces on the depth of immersion in water were obtained. The variants of the designs of vacuum contact devices with surfaces in the water environment are investigated, and the modernization of the laboratory test bench for testing vacuum contact devices under water is carried out.

scholarly journals Insights into the molecular mechanism for hyperpolarization-dependent activation of HCN channels

2018 ◽  
Vol 115 (34) ◽  
pp. E8086-E8095 ◽  
Author(s):  
Galen E. Flynn ◽  
William N. Zagotta
Keyword(s):  
Ion Channels ◽  
Cyclic Nucleotide ◽  
Electromechanical Coupling ◽  
Canonical Model ◽  
Hcn Channels ◽  
Voltage Gated ◽  
Kv Channels ◽  
Recovery From Inactivation ◽  
Voltage Dependent ◽  
Pore Domain

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels are both voltage- and ligand-activated membrane proteins that contribute to electrical excitability and pace-making activity in cardiac and neuronal cells. These channels are members of the voltage-gated Kv channel superfamily and cyclic nucleotide-binding domain subfamily of ion channels. HCN channels have a unique feature that distinguishes them from other voltage-gated channels: the HCN channel pore opens in response to hyperpolarizing voltages instead of depolarizing voltages. In the canonical model of electromechanical coupling, based on Kv channels, a change in membrane voltage activates the voltage-sensing domains (VSD) and the activation energy passes to the pore domain (PD) through a covalent linker that connects the VSD to the PD. In this investigation, the covalent linkage between the VSD and PD, the S4-S5 linker, and nearby regions of spHCN channels were mutated to determine the functional role each plays in hyperpolarization-dependent activation. The results show that: (i) the S4-S5 linker is not required for hyperpolarization-dependent activation or ligand-dependent gating; (ii) the S4 C-terminal region (S4C-term) is not necessary for ligand-dependent gating but is required for hyperpolarization-dependent activation and acts like an autoinhibitory domain on the PD; (iii) the S5N-term region is involved in VSD–PD coupling and holding the pore closed; and (iv) spHCN channels have two voltage-dependent processes, a hyperpolarization-dependent activation and a depolarization-dependent recovery from inactivation. These results are inconsistent with the canonical model of VSD–PD coupling in Kv channels and elucidate the mechanism for hyperpolarization-dependent activation of HCN channels.

scholarly journals Exploring Kv1.2 Channel Inactivation Through MD Simulations and Network Analysis

2021 ◽  
Vol 8 ◽  
Author(s):  
Flavio Costa ◽  
Carlo Guardiani ◽  
Alberto Giacomello
Keyword(s):  
Molecular Basis ◽  
Md Simulations ◽  
Childhood Epilepsy ◽  
Contact Map ◽  
Voltage Gated ◽  
Channel Inactivation ◽  
Inactivation Mechanism ◽  
Combined Simulation ◽  
Pore Domain ◽  
Voltage Sensor Domain

The KCNA2 gene encodes the Kv1.2 channel, a mammalian Shaker-like voltage-gated K+ channel, whose defections are linked to neuronal deficiency and childhood epilepsy. Despite the important role in the kinetic behavior of the channel, the inactivation remained hereby elusive. Here, we studied the Kv1.2 inactivation via a combined simulation/network theoretical approach that revealed two distinct pathways coupling the Voltage Sensor Domain and the Pore Domain to the Selectivity Filter. Additionally, we mutated some residues implicated in these paths and we explained microscopically their function in the inactivation mechanism by computing a contact map. Interestingly, some pathological residues shown to impair the inactivation lay on the paths. In summary, the presented results suggest two pathways as the possible molecular basis of the inactivation mechanism in the Kv1.2 channel. These pathways are consistent with earlier mutational studies and known mutations involved in neuronal channelopathies.

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