Ion Channels In Biological Membranes Research Articles

Acylated and alkylated benzo(crown-ethers) form ion-dependent ion channels in biological membranes

Synthetic ion channels based on benzo(crown-ether) compounds have been previously reported to function as ion-selective channels in planar lipid bilayers, with hydrogen bonding networks implicated in the formation of self-aggregated complexes. Herein, we report the synthesis and characterization of two new families of benzo(crown-ether) compounds, termed monoacylated and monoalkylated benzo(crown-ethers) (MABCE), both of which lack hydrogen bond donors. Depending on the length of alkyl chain substituent and the size of macrocycle, MABCE compounds inhibit bacterial growth and transport ions across biological membranes. Single-channel recordings show that the activity is higher in the presence of K+ as compared with Na+; however, under bionic conditions, open channels do not exhibit any preference between the two ions. These findings reveal that the ionic preference of benzo(crown-ether) compounds is either due to the regulation of assembly of ion-conducting supramolecular complexes or its membrane insertion by cations, as opposed to ion-selective transport through these scaffolds. Furthermore, our data show that the H-bonding network is not needed to form these assemblies in the membrane.

Interplay between Tumor Microenvironment and Cancer Cells.

Cancer cell interaction with microenvironment plays a very important role in cancer cell survival, proliferation, and/or metastasis. The cancer cell-microenvironment interaction is a highly complex process and has been one of the leading areas of research in cancer biology. Over the last decade, several components in tumor microenvironment have been identified to have a role in cancer cell survival, proliferation, or metastasis. The underlying mechanisms of tumor cell-microenvironment interactions have been investigated and exploited for cancer therapy. The present issue covers several aspects of cancer cell and tumor microenvironment. This issue contains interesting articles, which were accepted after a rigorous peer review process. The monocarboxylate transporters (MCTs) are proton-linked plasma membrane transporters that mediate transport of monocarboxylates such as pyruvate and lactate across cellular membranes. Tumor cells depend heavily on anaerobic glycolysis, which generates enormous amount of lactic acid as a byproduct. Lactic acid is toxic to cells and has to be excreted out of the cells through MCTs. An interesting meta-analysis paper by C. D. Bovenzi et al. showed the high expression of MCT4 and CD147 in multiple cancer cells. The elevated MCT4 and CD147 levels were strongly associated with poor overall survival of cancer patients. This work highlighted the importance of MCT4 and CD147 expression in several different cancers and establishes rationale for targeting these molecules for cancer therapy. As discussed above, as well as by several other reports, mostly the overabundance of ion channels in biological membranes has been implicated in pathogenesis of cancers. Only recently did few studies identify antitumor function of ion channels in some type of cancers. Interestingly, the paper by Z. Xia et al. showed the overexpression of potassium ions in liver cancer cells by the treatment with potassium ions that trigger cancer cell apoptosis, providing convincing evidence in favor of tumor suppression function of potassium ion channels in liver cancer. Given this, the levels of potassium ions in tumor microenvironment can influence the survival of liver cancer cells. Further investigation in this regard is warranted. Lymphatic vessels are integral part of tumor microenvironment. Although lymphatic vessels were mostly viewed as passive transporters of cancer cells, recent studies demonstrated the active role of these vessels in cancer metastasis. Indeed, these studies collectively established the rationale for targeting lymphangiogenesis for cancer treatment. The paper by X.-L. Ding et al. describes the antilymphangiogenesis effects of Gekko Sulfated Glycopeptide (GSPP) and discusses the potential therapeutic benefits of GSPP in colon carcinoma. The future studies could explore the translational potential of GSPP or related molecules in colon carcinoma or related cancers. The hormones play a key role in several types of cancers. Gender differences in hormone can influence several aspects of cancer. The paper by S. Caceres et al. developed a male mice xenograft model for mammary tumor and studied the impact of gender differences in hormones on mammary tumor cell proliferation and metastasis. Their preliminary analysis showed the less aggressive nature of mammary tumor cells in male mice compared to female. This work elaborates on the vast literature that describes the importance of extracellular hormone in tumor cell behavior. The traditional Chinese medicines are being used for cancer treatment for centuries. The review article by J. Xu et al. provides a very nice overview of the selected traditional Chinese medicines that suppress cancer cells by interfering with tumor microenvironment. This article also discusses the synergistic benefits of combining few selected traditional Chinese medicines. Collectively, this issue will advance our researchers and readers knowledge on various aspects of tumor cell-microenvironment interactions and will provide insight into new research focused in this area and potential therapeutic interventions. Kallesh D. Jayappa Ramesh C. Kovi Sumanta Chatterjee

Fluorescent labeling for patch-clamp fluorometry (PCF) measurements of real-time protein motion in ion channels.

Understanding the function of ion channels is a major goal of molecular neurophysiology. While standard electrophysiological methods are invaluable tools to investigate the gating of ion channels, the structural rearrangements that mediate the way a channel senses physiological signals and opens and closes its gates cannot be measured electrically in a direct way. Here, we describe a method, based on site-specific labeling of a channel of interest with an environmentally sensitive fluorophore, which makes it possible to monitor conformational changes of ion channels in biological membranes in real time.

Ion transport controlled by nanoparticle-functionalized membranes.

From proton exchange membranes in fuel cells to ion channels in biological membranes, the well-specified control of ionic interactions in confined geometries profoundly influences the transport and selectivity of porous materials. Here we outline a versatile new approach to control a membrane's electrostatic interactions with ions by depositing ligand-coated nanoparticles around the pore entrances. Leveraging the flexibility and control by which ligated nanoparticles can be synthesized, we demonstrate how ligand terminal groups such as methyl, carboxyl and amine can be used to tune the membrane charge density and control ion transport. Further functionality, exploiting the ligands as binding sites, is demonstrated for sulfonate groups resulting in an enhancement of the membrane charge density. We then extend these results to smaller dimensions by systematically varying the underlying pore diameter. As a whole, these results outline a previously unexplored method for the nanoparticle functionalization of membranes using ligated nanoparticles to control ion transport.

Individual Variability and Average Reliability in Parallel Networks of Heterogeneous Biological and Artificial Nanostructures

We simulate the collective electrical response of heterogeneous ensembles of biological and artificial nanostructures whose individual threshold potentials show a significant variability. This problem is of current interest because nanotechnology is bound to produce nanostructures with a significant experimental variability in their individual physical properties. This diversity is also present in biological systems that are however able to process information efficiently. The nanostructures considered are the ion channels of biological membranes, nanowire field-effect transistors, and metallic nanoparticle-based single electron transistors. These systems are simulated with canonical models that incorporate the basic threshold characteristics observed in the respective experimental current–voltage curves. In each case, the different shape, size, and charge distributions of the nanostructures result in statistical distributions for the individual threshold potentials, characterized by experimental average and width distribution values, rather than in identical replicates of the same unit. Despite the significant variability, the simulations suggest that useful average responses can still be achieved with summing networks of heterogeneous nanostructures because the collective behavior may compensate for individual failures and variability. Since threshold potential systems are commonplace in biology, the results obtained are also significant for understanding the role of diversity in biologically inspired networks.

Structural studies of biological membranes using ESEEM spectroscopy of spin labels and deuterium substitution

Electron Spin Echo Envelope Modulation (ESEEM) spectroscopy in conjunction with biochemical techniques of site-directed spin labeling and deuterium substitution in molecules or parts of molecules can be used to gain insights into supramolecular structure of biological membranes. The review covers the applications of this approach to study water penetration into the hydrophobic part of model phospholipid membranes and into the ion channels of biological membranes, to determine the localization and orientation of peptide antibiotics in membranes, and to investigate the conformations of enzymes and membrane proteins.

Recent progress in membrane protein structures and investigation methods

Tamir Gonen is a Group Leader at the Janelia Farm Research Campus of the Howard Hughes Medical Institute. Prior to his current position, he was an Associate Professor of Biochemistry and the Director of the Molecular Electron Microscopy Laboratory at the University of Washington in Seattle where he was also a Howard Hughes Medical Institute Early Career Scientist. His research aims are to understand the structure and function of membrane proteins involved in nutrient uptake, cellular communication, water uptake and homeostasis. His group is currently focusing on the structure and function of voltage gated ion channels in biological membranes by electron crystallography.

Processing weak electrical signals with threshold-potential nanostructures showing a high variability

We explore the processing of weak electrical signals in parallel arrays of bio-inspired threshold nanostructures showing a high variability in their threshold potentials. We consider a two-state canonical model that incorporates the basic properties demonstrated experimentally. The model is inspired by the voltage-gated ion channels in biological membranes and shows that the nanostructure variability can allow significant transmission of sub-threshold signals. Implications for the design of practical devices are briefly discussed.

Architecture of receptor-operated ion channels of biological membranes

Ion channels of biological membranes are the key proteins, which provide bioelectric functioning of living systems. These proteins are homo- or heterooligomers assembled from several identical or different subunits. Understanding the architectural organization and functioning of ion channels has been significantly extended due to resolving the crystal structure of several types of voltage-gated and receptor-operated channels. This review summarizes the information obtained from crystal structures of potassium, nicotinic acetylcholine receptor, P2X, and other ligand-gated ion channels. Despite the differences in the function, topology, ionic selectivity, and the subunit stoichiometry, a high similarity in the principles of organization of these macromolecular complexes has been revealed.

Attractive energy and entropy or particle size: the yin and yang of physical and biological science

It is well known that equilibrium in a thermodynamic system results from a competition or balance between lowering the energy and increasing the entropy, or at least the product of the temperature and entropy. This is remarkably similar to the Taoist concept of yin, a downward influence, and yang, an upward influence, where harmony is established by balancing yin and yang. Entropy is due to structure, which is largely determined by core repulsions or particle size whereas energy is largely determined by longer range attractive interactions. Here, this balance between energy and entropy or particle size is traced through the theory of simple fluids, begining with Andrews and van der Waals, the subsequent developments of perturbation theory, theories of correlation functions that are based on the Ornstein-Zernike relation and the mean spherical approximation, electrolytes, and recent work on ion channels in biological membranes, where the competition between energy and size gives an intuitively attractive explanation of the selectivity of cation channels. Simulations of complex systems, including proteins in aqueous solution, should be studied to determine the extent to which these concepts are useful for such situations.

Model of multifractal gating of single ionic channels in biological membranes

A physico-mathematical model of the gating machinery of single ionic channels in biological membranes has been developed. In the paradigm of this model, gating particles are subjected to: (i) deterministic friction force responsible for interactions of gating particles with the surrounding solution; (ii) deterministic potential force depending on the structure and conformational state of the channel pore (the latter is controlled by the transmembrane voltage V and regulates the motion of particles overcoming potential barriers on going from the closed (open) to the open (closed) state of the channel); (iii) deterministic force responsible for interactions of water molecules with hydrophobic sites in the channel pore, and, finally, (iv) stochastic thermal fluctuation force. The model affords adequate approximation of experimental data.

Memory in astrocytes: a hypothesis

BackgroundRecent work has indicated an increasingly complex role for astrocytes in the central nervous system. Astrocytes are now known to exchange information with neurons at synaptic junctions and to alter the information processing capabilities of the neurons. As an extension of this trend a hypothesis was proposed that astrocytes function to store information. To explore this idea the ion channels in biological membranes were compared to models known as cellular automata. These comparisons were made to test the hypothesis that ion channels in the membranes of astrocytes form a dynamic information storage device.ResultsTwo dimensional cellular automata were found to behave similarly to ion channels in a membrane when they function at the boundary between order and chaos. The length of time information is stored in this class of cellular automata is exponentially related to the number of units. Therefore the length of time biological ion channels store information was plotted versus the estimated number of ion channels in the tissue. This analysis indicates that there is an exponential relationship between memory and the number of ion channels. Extrapolation of this relationship to the estimated number of ion channels in the astrocytes of a human brain indicates that memory can be stored in this system for an entire life span. Interestingly, this information is not affixed to any physical structure, but is stored as an organization of the activity of the ion channels. Further analysis of two dimensional cellular automata also demonstrates that these systems have both associative and temporal memory capabilities.ConclusionIt is concluded that astrocytes may serve as a dynamic information sink for neurons. The memory in the astrocytes is stored by organizing the activity of ion channels and is not associated with a physical location such as a synapse. In order for this form of memory to be of significant duration it is necessary that the ion channels in the astrocyte syncytium be electrically in contact with each other. This function may be served by astrocyte gap junctions and suggests that agents that selectively block these gap junctions should disrupt memory.

About using the approximate fields to calculate the electrostatic potential distribution of membrane channels

By the example of gramicidine channel, a comparative analysis of different approximate representations (heavy atoms, polar protons, near-by atoms) of AMBER force field has been carried out to calculate the electrostatic potential distribution of ionic channels in biological membranes. The results obtained are compared with the potential computed in a full-atom representation. The use of approximate representations is shown to lead to estimated errors of the potential.

Power generation in random diode arrays

We discuss nonlinear disordered systems, random diode arrays (RDAs), which can represent such objects as large-area photovoltaics and ion channels of biological membranes. Our numerical modeling has revealed several interesting properties of RDAs. In particular, the geometrical distribution of nonuniformities across a RDA has only a minor effect on its integral characteristics determined by RDA parameter statistics. In the meantime, the dispersion of integral characteristics vs system size exhibits a nontrivial scaling dependence. Our theoretical interpretation here remains limited and is based on the picture of eddy currents flowing through weak diodes in the RDA.

Electrodiffusion Model Simulation of Ionic Channels: 1D Simulations

The drift-diffusion (Poisson-Nernst-Planck) model is applied to ionic channels in biological membranes plus surrounding solution baths. Simulations of the K channel in KCl solutions using the TRBDF2 method are presented which show significant boundary layers at the ends of the channel. The computed current-voltage curve for the K channel shows excellent agreement with experimental measurements.

Stochastic resonance in two-state model of membrane channel with comparable opening and closing rates.

Voltage-gated ion channels in biological membranes can be modeled as two-state stochastic systems with inter-state transition probabilities that depend on external stimulus. We study analytically the passage of a signal through such a system in the presence of external noise in the case when the above dependence is arbitrary, and illustrate our approach using the two models of ion channels known in the literature. The explicit expressions for the spectral density of the output signal and noise, the signal-to-noise ratio, and the coherence function are obtained for rectangular periodic signal and dichotomous noise in a wide range of parameters. The dependence of the above quantities on the bias and on the noise amplitude demonstrates strong resonant behavior in the regions where the probabilities of channel closing and opening become equal. This resonance results from additional symmetry between channel states and differs from conventional stochastic resonance studied earlier.

Deterministic model of ion channel flipping with fractal scaling of kinetic rates.

The flipping of ion channels in biological membranes has usually been modeled in terms of Markov transitions between open and closed states. The basic assumption of this approach is that channel flipping between open and closed states is an inherent stochastic process, due to random thermal fluctuations of units forming the channel protein. In this paper, we propose a different view of channel flipping, one not involving external stochastic causes. We consider the channel as a physical dynamic system, the unpredictable flipping of which is due to a deterministic mechanism which sustains a chaotic dynamics. In particular, we presume the changes in the channel conformation are due to delayed interaction between the ionic flow through the channel and the protein forming the channel. The model proposed here describes the channel by means of macroscopic physical quantities such as conductance, current, membrane, and reversal potentials and predicts open and closed dwell time distributions consisting of multiple exponential components and exhibiting power-law scaling over a wide range of time scales. The effective kinetic rate computed through use of simulation data shows fractal properties in good agreement with those seen experimentally. This mathematical model of the ion channel is physically consistent in terms of a plausible real system and may provide a novel key to understanding the complex behavior of the flipping process.

Ion channels of biological membranes: prediction of single channel conductance

The Poisson-Boltzmann equation was solved numerically for models of the pore regions of the Shaker K+ channel and of two glycoporins (LamB and ScrY) to yield electrostatic potential profiles along the pore axes. From these potential profiles, single-channel current-voltage (I–V) relations were calculated. The importance of a proper treatment of the ionisation state of two rings of aspartate sidechains at the mouth of the K+ channel pore emerged from such calculations. The calculated most likely state, in which only two of the eight aspartate sidechains were deprotonated, yielded better agreement with experimental conductance data. An approximate calculation of single-channel conductances based simply on pore geometry yielded very similar conductance values for the two glycoporins. This differed from an␣experimentally determined conductance ratio of ScrY:LamB=10:1. Preliminary electrostatics calculations appeared to reproduce the observed difference in conductance between the two glycoporins, confirming that single-channel conductance is determined by electrostatic as well as geometric considerations.

Ionic channels in biological membranes- electrostatic analysis of a natural nanotube

Ionic channels are proteins with holes down their middle that control access to biological cells and thus govern an enormous range of biological functions important in health and disease. A substantial fraction of the drugs used in clinical medicine act directly or indirectly on channels. Channels have a simple well-defined structure, and the fundamental mechanism of ionic motion is known to be electrodiffusion. The current through individual channel molecules can easily be measured, and is in fact measured in hundreds if not thousands of laboratories everyday. Thus, ionic channels are ideal objects for physical investigation: on the one hand, they are well-defined structures following simple physics, on the other hand they are of general biological importance. A simple theory of ion permeation through a channel is presented, in which diffusion occurs according to Fick's law and drift according to Ohm's law, in the electric field determined by all the charges present. This theory accounts for permeation in the channels studied to date in a wide range of solutions. Interestingly, the theory works because the shape of the electric field is a sensitive function of experimental conditions, e.g. ion concentration. Rate constants for flux are sensitive functions of ionic concentration because the fixed charge of the channel protein is shielded by the ions in and near it. Such shielding effects are not included in traditional theories of ionic channels, or other proteins, for that matter.

Ionic Channels in Biological Membranes: Natural Nanotubes Described by the Drift-Diffusion Equations

An important class of biological molecules-proteins called ionic channels–conduct ions (like Na+, K+, Cl-) through a narrow tunnel of fixed charge (‘doping’). Ionic channels are the main pathway by which substances move into cells and so are of great biological and medical importance: a substantial fraction of all drugs used by physicians act on channels. Channels can be studied in the tradition of computational electronics. Drift diffusion equations form an adequate model of IV relations of 6 different channel proteins in ̴ 10 solutions over ±150 mV. Ionic channels can also be studied with the powerful techniques of molecular biology. Atoms can be modified one at a time and the location of every atom can be determined. Ionic channels are natural nanotubes that can be controlled more precisely and easily than physical nanostructures but biologists need help if realistic simulations are to be done atomic detail.