scholarly journals Theory and Experiments on Multi-Ion Permeation and Selectivity in the NaChBac Ion Channel

2019 ◽  
Vol 18 (02) ◽  
pp. 1940007 ◽  
Author(s):  
W. A. T. Gibby ◽  
M. L. Barabash ◽  
C. Guardiani ◽  
D. G. Luchinsky ◽  
O. A. Fedorenko ◽  
...  
Keyword(s):  
Statistical Theory ◽  
Ion Channels ◽  
Kinetic Model ◽  
Ion Channel ◽  
Linear Response ◽  
Unsolved Problem ◽  
Ion Permeation ◽  
Self Consistent ◽  
Self Consistency ◽  
Theory And Experiments

The highly selective permeation of ions through biological ion channels is an unsolved problem of noise and fluctuations. In this paper, we motivate and introduce a non-equilibrium and self-consistent multi-species kinetic model, with the express aims of comparing with experimental recordings of current versus voltage and concentration and extracting important permeation parameters. For self-consistency, the behavior of the model at the two-state, i.e., selective limit in linear response, must agree with recent results derived from an equilibrium statistical theory. The kinetic model provides a good fit to data, including the key result of an anomalous mole fraction effect.

Ion Channel Permeation and Selectivity

2019 ◽  
Author(s):  
Juan J. Nogueira ◽  
Ben Corry
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Ion Selectivity ◽  
Ionic Currents ◽  
Biological Processes ◽  
Ion Permeation ◽  
Voltage Gated ◽  
Physical Mechanisms ◽  
Theoretical Approaches ◽  
Mechanistic Insight

Many biological processes essential for life rely on the transport of specific ions at specific times across cell membranes. Such exquisite control of ionic currents, which is regulated by protein ion channels, is fundamental for the proper functioning of the cells. It is not surprising, therefore, that the mechanism of ion permeation and selectivity in ion channels has been extensively investigated by means of experimental and theoretical approaches. These studies have provided great mechanistic insight but have also raised new questions that are still unresolved. This chapter first summarizes the main techniques that have provided significant knowledge about ion permeation and selectivity. It then discusses the physical mechanisms leading to ion permeation and the explanations that have been proposed for ion selectivity in voltage-gated potassium, sodium, and calcium channels.

scholarly journals A generalized kinetic model describes ion-permeation mechanisms in various ion channels

2021 ◽  
Author(s):  
Di Wu
Keyword(s):  
Ion Channels ◽  
Kinetic Model ◽  
Patch Clamp ◽  
Cellular Responses ◽  
Ion Permeation ◽  
Patch Clamp Recording ◽  
Boltzmann Factor ◽  
Current Voltage ◽  
Test Voltage ◽  
Generalized Kinetic Model

Ion channels conduct various ions across biological membranes to maintain the membrane potential, to transmit the electrical signals, and to elicit the subsequent cellular responses by the signaling ions. Ion channels differ in their capabilities to select and conduct ions, which can be studied by the patch-clamp recording method that compares the current traces responding to the test voltage elicited at different conditions. In these experiments, the current-voltage curves are usually fitted by a sigmoidal function containing the Boltzmann factor. This equation is quite successful in fitting the experimental data in many cases, but it also fails in several others. Regretfully, some useful information may be lost in these data, which otherwise can reveal the ion-permeation mechanisms. Here we present a generalized kinetic model that captures the essential features of the current-voltage relations and describes the simple mechanism of the ion permeation through different ion channels. We demonstrate that this model is capable to fit various types of the patch-clamp data and explain their ion-permeation mechanisms.

scholarly journals A Heuristic Derived from Analysis of the Ion Channel Structural Proteome Permits the Rapid Identification of Hydrophobic Gates

2018 ◽  
Author(s):  
Shanlin Rao ◽  
Gianni Klesse ◽  
Phillip J. Stansfeld ◽  
Stephen J. Tucker ◽  
Mark S.P. Sansom
Keyword(s):  
Machine Learning ◽  
Ion Channels ◽  
Ion Channel ◽  
Functional State ◽  
Conformational Changes ◽  
Rapid Identification ◽  
Ion Permeation ◽  
Ionic Flux ◽  
Easy Method ◽  
Channel Structures

AbstractIon channel proteins control ionic flux across biological membranes through conformational changes in their transmembrane pores. An exponentially increasing number of channel structures captured in different conformational states are now being determined. However, these newly-resolved structures are commonly classified as either open or closed based solely on the physical dimensions of their pore and it is now known that more accurate annotation of their conductive state requires an additional assessment of the effect of pore hydrophobicity. A narrow hydrophobic gate region may disfavour liquid-phase water, leading to local de-wetting which will form an energetic barrier to water and ion permeation without steric occlusion of the pore. Here we quantify the combined influence of radius and hydrophobicity on pore de-wetting by applying molecular dynamics simulations and machine learning to nearly 200 ion channel structures. This allows us to propose a simple simulation-free heuristic model that rapidly and accurately predicts the presence of hydrophobic gates. This not only enables the functional annotation of new channel structures as soon as they are determined, but may also facilitate the design of novel nanopores controlled by hydrophobic gates.Significance statementIon channels are nanoscale protein pores in cell membranes. An exponentially increasing number of structures for channels means that computational methods for predicting their functional state are needed. Hydrophobic gates in ion channels result in local de-wetting of pores which functionally closes them to water and ion permeation. We use simulations of water behaviour within nearly 200 different ion channel structures to explore how the radius and hydrophobicity of pores determine their hydration vs. de-wetting behaviour. Machine learning-assisted analysis of these simulations enables us to propose a simple model for this relationship. This allows us to present an easy method for the rapid prediction of the functional state of new channel structures as they emerge.

scholarly journals The structure of a potassium-selective ion channel reveals a hydrophobic gate regulating ion permeation

IUCrJ ◽  
2020 ◽  
Vol 7 (5) ◽  
pp. 835-843
Author(s):  
Patricia S. Langan ◽  
Venu Gopal Vandavasi ◽  
Wojciech Kopec ◽  
Brendan Sullivan ◽  
Pavel V. Afonne ◽  
...  
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Conformational Transition ◽  
Transmembrane Proteins ◽  
Selectivity Filter ◽  
Ion Permeation ◽  
Hydrophobic Residue ◽  
Ion Flow ◽  
Flow Through ◽  
Resolution Structure

Protein dynamics are essential to function. One example of this is the various gating mechanisms within ion channels, which are transmembrane proteins that act as gateways into the cell. Typical ion channels switch between an open and closed state via a conformational transition which is often triggered by an external stimulus, such as ligand binding or pH and voltage differences. The atomic resolution structure of a potassium-selective ion channel named NaK2K has allowed us to observe that a hydrophobic residue at the bottom of the selectivity filter, Phe92, appears in dual conformations. One of the two conformations of Phe92 restricts the diameter of the exit pore around the selectivity filter, limiting ion flow through the channel, while the other conformation of Phe92 provides a larger-diameter exit pore from the selectivity filter. Thus, it can be concluded that Phe92 acts as a hydrophobic gate, regulating the flow of ions through the selectivity filter.

A First Principles Approach for Partitioning Linear Response Properties into Additive and Cooperative Contributions

2018 ◽  
Author(s):  
Daniel Lambrecht ◽  
Eric Berquist
Keyword(s):  
First Principles ◽  
Linear Response ◽  
Building Blocks ◽  
Field Method ◽  
Response Property ◽  
Response Properties ◽  
Consistent Field ◽  
Molecular Building Blocks ◽  
Self Consistent ◽  
Self Consistent Field

We present a first principles approach for decomposing molecular linear response properties into orthogonal (additive) plus non-orthogonal/cooperative contributions. This approach enables one to 1) identify the contributions of molecular building blocks like functional groups or monomer units to a given response property and 2) quantify cooperativity between these contributions. In analogy to the self consistent field method for molecular interactions, SCF(MI), we term our approach LR(MI). The theory, implementation and pilot data are described in detail in the manuscript and supporting information.

scholarly journals On the Importance of Atomic Fluctuations, Protein Flexibility, and Solvent in Ion Permeation

2004 ◽  
Vol 124 (6) ◽  
pp. 679-690 ◽  
Author(s):  
Toby W. Allen ◽  
O.S. Andersen ◽  
Benoit Roux
Keyword(s):  
Ion Channel ◽  
Protein Function ◽  
Channel Model ◽  
Protein Structures ◽  
Thermal Fluctuations ◽  
Model Parameters ◽  
Ion Permeation ◽  
Model Calculations ◽  
Channel Interactions ◽  
Solvent Molecules

Proteins, including ion channels, often are described in terms of some average structure and pictured as rigid entities immersed in a featureless solvent continuum. This simplified view, which provides for a convenient representation of the protein's overall structure, incurs the risk of deemphasizing important features underlying protein function, such as thermal fluctuations in the atom positions and the discreteness of the solvent molecules. These factors become particularly important in the case of ion movement through narrow pores, where the magnitude of the thermal fluctuations may be comparable to the ion pore atom separations, such that the strength of the ion channel interactions may vary dramatically as a function of the instantaneous configuration of the ion and the surrounding protein and pore water. Descriptions of ion permeation through narrow pores, which employ static protein structures and a macroscopic continuum dielectric solvent, thus face fundamental difficulties. We illustrate this using simple model calculations based on the gramicidin A and KcsA potassium channels, which show that thermal atomic fluctuations lead to energy profiles that vary by tens of kcal/mol. Consequently, within the framework of a rigid pore model, ion-channel energetics is extremely sensitive to the choice of experimental structure and how the space-dependent dielectric constant is assigned. Given these observations, the significance of any description based on a rigid structure appears limited. Creating a conducting channel model from one single structure requires substantial and arbitrary engineering of the model parameters, making it difficult for such approaches to contribute to our understanding of ion permeation at a microscopic level.

scholarly journals TOK Homologue in Neurospora crassa: First Cloning and Functional Characterization of an Ion Channel in a Filamentous Fungus

2003 ◽  
Vol 2 (1) ◽  
pp. 181-190 ◽  
Author(s):  
Stephen K. Roberts
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Neurospora Crassa ◽  
Filamentous Fungus ◽  
Single Channel ◽  
Functional Characterization ◽  
Reversal Potential ◽  
Channel Activity ◽  
Biophysical Properties ◽  
Patch Clamp Technique

ABSTRACT In contrast to animal and plant cells, very little is known of ion channel function in fungal physiology. The life cycle of most fungi depends on the “filamentous” polarized growth of hyphal cells; however, no ion channels have been cloned from filamentous fungi and comparatively few preliminary recordings of ion channel activity have been made. In an attempt to gain an insight into the role of ion channels in fungal hyphal physiology, a homolog of the yeast K+ channel (ScTOK1) was cloned from the filamentous fungus, Neurospora crassa. The patch clamp technique was used to investigate the biophysical properties of the N. crassa K+ channel (NcTOKA) after heterologous expression of NcTOKA in yeast. NcTOKA mediated mainly time-dependent outward whole-cell currents, and the reversal potential of these currents indicated that it conducted K+ efflux. NcTOKA channel gating was sensitive to extracellular K+ such that channel activation was dependent on the reversal potential for K+. However, expression of NcTOKA was able to overcome the K+ auxotrophy of a yeast mutant missing the K+ uptake transporters TRK1 and TRK2, suggesting that NcTOKA also mediated K+ influx. Consistent with this, close inspection of NcTOKA-mediated currents revealed small inward K+ currents at potentials negative of EK. NcTOKA single-channel activity was characterized by rapid flickering between the open and closed states with a unitary conductance of 16 pS. NcTOKA was effectively blocked by extracellular Ca2+, verapamil, quinine, and TEA+ but was insensitive to Cs+, 4-aminopyridine, and glibenclamide. The physiological significance of NcTOKA is discussed in the context of its biophysical properties.

Ion channel activities of cultured rat mesangial cells

1991 ◽  
Vol 261 (5) ◽  
pp. F808-F814 ◽  
Author(s):  
H. Matsunaga ◽  
N. Yamashita ◽  
Y. Miyajima ◽  
T. Okuda ◽  
H. Chang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Ion Channels ◽  
Patch Clamp ◽  
Ion Channel ◽  
Arginine Vasopressin ◽  
Mesangial Cells ◽  
Cation Channel ◽  
K Channel ◽  
Patch Clamp Technique ◽  
Inside Out

We used the patch-clamp technique to clarify the nature of ion channels in renal mesangial cells in culture. In the cell-attached mode most patches were silent in the absence of agonists. In some patches a 25-pS nonselective channel was observed. This 25-pS cation channel was consistently observed in inside-out patches, and it was activated by intracellular Ca2+. Excised patch experiments also revealed the existence of a 40-pS K+ channel, which was activated by intracellular Ca2+. This 40-pS K+ channel was observed infrequently in the cell-attached mode. The activities of both channels were increased by arginine vasopressin or angiotensin II, resulting from an increase in intracellular Ca2+ concentration.

scholarly journals Proper Voltage-Dependent Ion Channel Function in Dysferlin-Deficient Cardiomyocytes

2015 ◽  
Vol 36 (3) ◽  
pp. 1049-1058 ◽  
Author(s):  
Lena Rubi ◽  
Vaibhavkumar S. Gawali ◽  
Helmut Kubista ◽  
Hannes Todt ◽  
Karlheinz Hilber ◽  
...  
Keyword(s):  
Ion Channels ◽  
Muscular Dystrophy ◽  
Ion Channel ◽  
Cardiac Electrophysiology ◽  
Cardiac Complications ◽  
Membrane Repair ◽  
Patch Clamp Technique ◽  
Cardiac Ion Channels ◽  
Ventricular Cardiomyocytes ◽  
Voltage Dependent

Background/Aims: Dysferlin plays a decisive role in calcium-dependent membrane repair in myocytes. Mutations in the encoding DYSF gene cause a number of myopathies, e.g. limb-girdle muscular dystrophy type 2B (LGMD2B). Besides skeletal muscle degenerative processes, dysferlin deficiency is also associated with cardiac complications. Thus, both LGMD2B patients and dysferlin-deficient mice develop a dilated cardiomyopathy. We and others have recently reported that dystrophin-deficient ventricular cardiomyocytes from mouse models of Duchenne muscular dystrophy show significant abnormalities in voltage-dependent ion channels, which may contribute to the pathophysiology in dystrophic cardiomyopathy. The aim of the present study was to investigate if dysferlin, like dystrophin, is a regulator of cardiac ion channels. Methods and Results: By using the whole cell patch-clamp technique, we compared the properties of voltage-dependent calcium and sodium channels, as well as action potentials in ventricular cardiomyocytes isolated from the hearts of normal and dysferlin-deficient (dysf) mice. In contrast to dystrophin deficiency, the lack of dysferlin did not impair the ion channel properties and left action potential parameters unaltered. In connection with normal ECGs in dysf mice these results suggest that dysferlin deficiency does not perturb cardiac electrophysiology. Conclusion: Our study demonstrates that dysferlin does not regulate cardiac voltage-dependent ion channels, and implies that abnormalities in cardiac ion channels are not a universal characteristic of all muscular dystrophy types.

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