Ion Channel Modeling beyond State of the Art: A Comparison with a System Theory-Based Model of the Shaker-Related Voltage-Gated Potassium Channel Kv1.1

The mathematical modeling of ion channel kinetics is an important tool for studying the electrophysiological mechanisms of the nerves, heart, or cancer, from a single cell to an organ. Common approaches use either a Hodgkin–Huxley (HH) or a hidden Markov model (HMM) description, depending on the level of detail of the functionality and structural changes of the underlying channel gating, and taking into account the computational effort for model simulations. Here, we introduce for the first time a novel system theory-based approach for ion channel modeling based on the concept of transfer function characterization, without a priori knowledge of the biological system, using patch clamp measurements. Using the shaker-related voltage-gated potassium channel Kv1.1 (KCNA1) as an example, we compare the established approaches, HH and HMM, with the system theory-based concept in terms of model accuracy, computational effort, the degree of electrophysiological interpretability, and methodological limitations. This highly data-driven modeling concept offers a new opportunity for the phenomenological kinetic modeling of ion channels, exhibiting exceptional accuracy and computational efficiency compared to the conventional methods. The method has a high potential to further improve the quality and computational performance of complex cell and organ model simulations, and could provide a valuable new tool in the field of next-generation in silico electrophysiology.

Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels

Lipids modulate the function of many ion channels, possibly through direct lipid-protein interactions. The recent outpouring of ion channel structures by cryo-EM has revealed many lipid binding sites. Whether these sites mediate lipid modulation of ion channel function is not firmly established in most cases. However, it is intriguing that many of these lipid binding sites are also known sites for other allosteric modulators or drugs, supporting the notion that lipids act as endogenous allosteric modulators through these sites. Here, we review such lipid-drug binding sites, focusing on pentameric ligand-gated ion channels and transient receptor potential channels. Notable examples include sites for phospholipids and sterols that are shared by anesthetics and vanilloids. We discuss some implications of lipid binding at these sites including the possibility that lipids can alter drug potency or that understanding protein-lipid interactions can guide drug design. Structures are only the first step toward understanding the mechanism of lipid modulation at these sites. Looking forward, we identify knowledge gaps in the field and approaches to address them. These include defining the effects of lipids on channel function in reconstituted systems using asymmetric membranes and measuring lipid binding affinities at specific sites using native mass spectrometry, fluorescence binding assays, and computational approaches.

Noninvasive Near-Infrared Light Triggers Remote Activation of Thermo-Responsive TRPV1 Channels in Neurons Based on Biodegradable/Photothermal Polymer Micelles

In this study, we developed a novel biodegradable/photothermal polymer micelle-based remote-activation method for a temperature-sensitive ion channel, namely transient receptor potential cation channel subfamily V member 1 (TRPV1). Biodegradable/photothermal polymer...

INSTRUCTION TOOLS FOR SIGNAL PROCESSING AND MACHINE LEARNING FOR ION-CHANNEL SENSORS

Ion Channel sensors have several applications including DNA sequencing, biothreat detection, and medical applications. Ion-channel sensors mimic the selective transport mechanism of cell membranes and can detect a wide range of analytes at the molecule level. Analytes are sensed through changes in signal patterns. Papers in the literature have described different methods for ion channel signal analysis. In this paper, we describe a series of new graphical tools for ion channel signal analysis which can be used for research and education. The paper focuses on the utility of this tools in biosensor classes. Teaching signal processing and machine learning for ion channel sensors is challenging because of the multidisciplinary content and student backgrounds which include physics, chemistry, biology and engineering. The paper describes graphical ion channel analysis tools developed for an on-line simulation environment called J-DSP. The tools are integrated and assessed in a graduate bio-sensor course through computer laboratory exercises.

Investigating the mechanotransduction of transient shear stress mediated by Piezo1 ion channel using a 3D printed dynamic gravity pump

Microfluidic systems are widely used for studying the mechanotransduction of flow-induced shear stress in mechanosensitive cells. However, these studies are generally performed under constant flow rates, mainly, due to the...