Biophysics and Nanotechnology of Ion Channels

Mohammad Ashrafuzzaman

• Publisher: CRC Press
• Year: 2021
• ISBN:
  9781000451641
• Edition: 1
• Topic: Ciencias biológicas
• Subtopic: Biofísica

This book provides a comprehensive review of the biophysics and nanotechnology of ion channels. It details the biological and physiological entities of ion channels in cells and addresses various physical perspectives of ion channel structures and functions. Naturally inbuilt and artificial applicable nanotechnologies of ion channels are modelled and explored. It discusses various methods that can be utilized toward understanding ion channel-based cellular diseases.

Physical, biochemical, biomedical, and bioinformatics techniques are taken into consideration to enable the development of strategies to address therapeutic drug discovery and delivery.

This book will be of interest to advanced undergraduate and graduate students in biophysics and related biomedical sciences in addition to researchers in the field and industry.

Features:

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• Provides a stimulating introduction to the structures and functions of ion channels of biological cell membranes and discusses the biophysics of ion channels in condensed matter state and physiological condition

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• Addresses natural processes and nanotechnology opportunities for their purposeful manipulation

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• Lays the groundwork for vitally important medical advances

Mohammad Ashrafuzzaman, a biophysicist and condensed matter scientist, is passionate about investigating biological and biochemical processes utilizing the principles and techniques of physics. He is an associate professor at King Saud University's Biochemistry Department of College of Science, Riyadh, Saudi Arabia, the co-founder of MDT Canada Inc., and the founder of Child Life Development Institute, Edmonton, Canada. He also authored Nanoscale Biophysics of the Cell and Membrane Biophysics.

1 Ion Channels – Physical Structures and Gating Mechanisms

DOI: 10.1201/9781003010654-1

Ion channels are transporters of materials and electrolytes across membranes. The channels also act as communicators between regions on both sides of the membrane. Generally, they play crucial roles in modestly compromising to breaking the membrane’s physical barriers against materials and information. The exchange of electrolytes, water molecules, nutrients, proteins, genetic materials, etc. across semi-permeable membranes of biological cells is a dynamic, yet active or passive transport phenomenon. Ion channels are membrane proteins that have specific and/or nonspecific participation in maintaining the membrane exchange phenomena following physical energetics principles. Statistical mechanics principles consider energetics of the structural channel integrity, fluctuations, and transitions among various physical states inside the lipid membrane, and thus channel functions are determined. Ion channels have mainly two physical states, namely, closed or inactive and open or active state. The distinction between these two states is clear considering their ability to transport electrolytes across the membrane. However, therte are additional physical states that might be considered from the viewpoint of crucial energetics of the channel conformations. This chapter aims to explain all the structural, energetics, and phenomenological aspects of various types of channels falling under different categories. We shall try to generalize their structural and functional similarities and dissimilarities. Biological and biophysical inspections will guide us to addressing the channels regarding their natural physiological states and roles, mutations due to disease or genetic conditions, and possible natural and artificial intervention strategies.

1.1 Introduction to General Aspects of Channels

Ion channels are cell membrane-hosted physical structures that help the membrane to be selectively permeable to certain ions. Channels are constructed because of interactions among membrane proteins and membrane constituents, especially lipids. Local hydrophobic and hydrophilic environments of the membrane and the transmembrane electrical and thermodynamic conditions have leading roles in helping the channels to get constructed and remain stable and undergo transitions between different energy states. The channel constituents and channels themselves are dynamic in membrane environment following statistical mechanical principles to transit from one energy state to another led by energetics. Ion channels are considered to fluctuate between stable, quasi-stable, and unstable states. During the stable open state (OS) of ion channels, a specific amount of ions are allowed to cross through the channels under a transmembrane potential, determining the conductance of the channel. As the channel structure transfers to a different open or close state, the conductance gets altered to another value (corresponding to open state) or zero (corresponding to the close state). This is the simplistic phenomenological interpretation based on the electrophysiological (EP) measurements of channel currents. Figure 1.1 depicts the scenario for two simple channels (Ashrafuzzaman et al., 2008).

FIGURE 1.1 Current fluctuations (in EP records) through two simple channels: β–helical gramicidin A (gA) and barrel-save alamethicin (Alm) channels/pores in model membrane. A 10 s gA current trace across phosphatidylcholine bilayer under the influence of 200 mV transbilayer potential and a 0.26 s Alm channel current trace across identical bilayer under influence of 150 mV transbilayer potential are presented here. For details, see Ashrafuzzaman et al. (2008).

Ion channel currents are determined by mainly the ion concentration difference across the membrane hosting the channels and the diffusive transport of the ions toward the channels and away from them. Calculating the ion channel currents requires solving the diffusion equation around the channels. Bentele and Falcke (2007) provided a quasi-steady approximation for the channel current and the local concentrations at the channel together with formulas linking the channel current and local concentrations at the channel to bulk concentrations and diffusion properties of the compartments. The quasi-steady approximation correlates currents with the bulk concentrations and provides formulas for the local concentrations. Thus, it provides a tool for the experimental analysis of in vivo currents and concentrations if the values of the relevant parameters in the formulas are known. For details on the models and associated equations, readers should consult the original article. Their hypothesis was that the knowledge about the concentration gradients around transport molecules may be required for modeling by the presence of the regulatory binding sites for conducted ions within the range of large gradients. That should apply to all ion channels regulated by the ions they conduct and to communicate with other compartments, channels, or chemical species. However, the in vivo ion channel current measurements started long before this kind of pinpointed theoretical understanding. Almost a century ago, voltage-clamp techniques were developed and applied in understanding membrane potentials. This technique allows the membrane voltage to be manipulated independent of the ionic currents, which allows us to study the current-voltage relationships of membrane-hosted channels.

During the 1940s, Kenneth Cole and George Mormont started to develop the voltage-clamp technique, where the large cell membrane potential could be measured and controlled. This led to the earliest descriptions of the membrane electrical properties and specifically the conductance that underlie neuronal action potentials. Within two decades, Alan Hodgkin and Andrew Huxley started creating grounds and finally refined the technique to only discover that the action potential was not simply a relaxation of the membrane potential to zero, but constituted an overshoot of the membrane potential to positive potentials. They also discovered that the action potential depolarizing phase was due to sodium (Na⁺) flux into the cell and the repolarization back to the resting membrane potential was due to potassium (K⁺) efflux. Thus, the concept of channels (sodium and potassium channels) emerged with a considerable level of understanding. This is one of the early breakthroughs modern medical science celebrates and will never forget in the coming future.

The two electrodes that Cole, Hodgkin, and Huxley used were fine wires that could be inserted only into extremely large cells, for example, the squid giant axon approximately 1 mm in diameter. Scientists were not able to stop there as they had to inspect at smaller resolutions, for example, at the cell membrane scale which is of the order of low nanometer (~5 nm) thickness.

In the 1980s, new cell-based electrical conductance were discovered, including voltage- and ligand-gated conductance. The confirmation of voltage- and ligand-gated pores constructed by distinct proteins naturally required another technological breakthrough, which came on the shoulders of Bert Sakmann, Erwin Neher, and colleagues who developed the patch-clamp technique. They demonstrated that a very high resistance, of the order of Giga ohm (GΩ), a seal could be formed between a glass micropipette and cell’s plasma membrane. Thus, the voltage-clamp technique could be applied to much smaller cells and even to small patches of the membrane, occasionally containing a single-channel protein. Now electrophysiology recording (EPR) of single ion channel currents is obvious research using the patch-clamp technique. Biophysics of ion channels has emerged as a unique subject based on mainly a bulk amount of research and discoveries using especially the experimental voltage-clamp and patch-clamp techniques. The function of channel protein molecules can now be monitored in real time. Thus, the statistical nature of the channel is observed.

During the 1980s and 1990s, the theoretical and computational research to explore the kinematics of ion channels in dynamic membrane systems started gaining popularity. In silico modeling alongside general theoretical and experimental analysis of ion channel functions helped understand channel conformational energetics and energetics of the flow of charges through channels. Martin Karplus, Arieh Warshel, and Michael Levitt are among the best modern-day scientists who revolutionized areas like multiscale methods for various biological complex systems. They developed methods and found their applications in silico simulating the behavior of molecules at various biologically relevant scales, ranging from single molecules to proteins. These simulations helped address the behavior of the channels in plasma membran...