Classification Of Ion Channels Research Articles

Dynamic molecular portraits of ion-conducting pores characterize functional states of TRPV channels

Structural biology is solving an ever-increasing number of snapshots of ion channel conformational ensembles. Deciphering ion channel mechanisms, however, requires understanding the ensemble dynamics beyond the static structures. Here, we present a molecular modeling-based approach characterizing the ion channel structural intermediates, or their “dynamic molecular portraits”, by assessing water and ion conductivity along with the detailed evaluation of pore hydrophobicity and residue packing. We illustrate the power of this approach by analyzing structures of few vanilloid-subfamily transient receptor potential (TRPV) channels. Based on the pore architecture, there are three major states that are common for TRPVs, which we call α-closed, π-closed, and π-open. We show that the pore hydrophobicity and residue packing for the open state is most favorable for the pore conductance. On the contrary, the α-closed state is the most hydrophobic and always non-conducting. Our approach can also be used for structural and functional classification of ion channels.

Exploiting protein language models for the precise classification of ion channels and ion transporters.

This study introduces TooT-PLM-ionCT, a comprehensive framework that consolidates three distinct systems, each meticulously tailored for one of the following tasks: distinguishing ion channels (ICs) from membrane proteins (MPs), segregating ion transporters (ITs) from MPs, and differentiating ICs from ITs. Drawing upon the strengths of six Protein Language Models (PLMs)-ProtBERT, ProtBERT-BFD, ESM-1b, ESM-2 (650M parameters), and ESM-2 (15B parameters), TooT-PLM-ionCT employs a combination of traditional classifiers and deep learning models for nuanced protein classification. Originally validated on an existing dataset by previous researchers, our systems demonstrated superior performance in identifying ITs from MPs and distinguishing ICs from ITs, with the IC-MP discrimination achieving state-of-the-art results. In light of recommendations for additional validation, we introduced a new dataset, significantly enhancing the robustness and generalization of our models across bioinformatics challenges. This new evaluation underscored the effectiveness of TooT-PLM-ionCT in adapting to novel data while maintaining high classification accuracy. Furthermore, this study explores critical factors affecting classification accuracy, such as dataset balancing, the impact of using frozen versus fine-tuned PLM representations, and the variance between half and full precision in floating-point computations. To facilitate broader application and accessibility, a web server (https://tootsuite.encs.concordia.ca/service/TooT-PLM-ionCT) has been developed, allowing users to evaluate unknown protein sequences through our specialized systems for IC-MP, IT-MP, and IC-IT classification tasks.

To Be or Not to Be an Ion Channel: Cryo-EM Structures Have a Say.

Ion channels are the second largest class of drug targets after G protein-coupled receptors. In addition to well-recognized ones like voltage-gated Na/K/Ca channels in the heart and neurons, novel ion channels are continuously discovered in both excitable and non-excitable cells and demonstrated to play important roles in many physiological processes and diseases such as developmental disorders, neurodegenerative diseases, and cancer. However, in the field of ion channel discovery, there are an unignorable number of published studies that are unsolid and misleading. Despite being the gold standard of a functional assay for ion channels, electrophysiological recordings are often accompanied by electrical noise, leak conductance, and background currents of the membrane system. These unwanted signals, if not treated properly, lead to the mischaracterization of proteins with seemingly unusual ion-conducting properties. In the recent ten years, the technical revolution of cryo-electron microscopy (cryo-EM) has greatly advanced our understanding of the structures and gating mechanisms of various ion channels and also raised concerns about the pore-forming ability of some previously identified channel proteins. In this review, we summarize cryo-EM findings on ion channels with molecular identities recognized or disputed in recent ten years and discuss current knowledge of proposed channel proteins awaiting cryo-EM analyses. We also present a classification of ion channels according to their architectures and evolutionary relationships and discuss the possibility and strategy of identifying more ion channels by analyzing structures of transmembrane proteins of unknown function. We propose that cross-validation by electrophysiological and structural analyses should be essentially required for determining molecular identities of novel ion channels.

Recent Advances in Computer-Aided Structure-Based Drug Design on Ion Channels.

Ion channels play important roles in fundamental biological processes, such as electric signaling in cells, muscle contraction, hormone secretion, and regulation of the immune response. Targeting ion channels with drugs represents a treatment option for neurological and cardiovascular diseases, muscular degradation disorders, and pathologies related to disturbed pain sensation. While there are more than 300 different ion channels in the human organism, drugs have been developed only for some of them and currently available drugs lack selectivity. Computational approaches are an indispensable tool for drug discovery and can speed up, especially, the early development stages of lead identification and optimization. The number of molecular structures of ion channels has considerably increased over the last ten years, providing new opportunities for structure-based drug development. This review summarizes important knowledge about ion channel classification, structure, mechanisms, and pathology with the main focus on recent developments in the field of computer-aided, structure-based drug design on ion channels. We highlight studies that link structural data with modeling and chemoinformatic approaches for the identification and characterization of new molecules targeting ion channels. These approaches hold great potential to advance research on ion channel drugs in the future.

Scorpion Peptides and Ion Channels: An Insightful Review of Mechanisms and Drug Development.

The Buthidae family of scorpions consists of arthropods with significant medical relevance, as their venom contains a diverse range of biomolecules, including neurotoxins that selectively target ion channels in cell membranes. These ion channels play a crucial role in regulating physiological processes, and any disturbance in their activity can result in channelopathies, which can lead to various diseases such as autoimmune, cardiovascular, immunological, neurological, and neoplastic conditions. Given the importance of ion channels, scorpion peptides represent a valuable resource for developing drugs with targeted specificity for these channels. This review provides a comprehensive overview of the structure and classification of ion channels, the action of scorpion toxins on these channels, and potential avenues for future research. Overall, this review highlights the significance of scorpion venom as a promising source for discovering novel drugs with therapeutic potential for treating channelopathies.

KCNE1 is an auxiliary subunit of two distinct ion channel superfamilies

Determination of what is the specificity of subunits composing a protein complex is essential when studying gene variants on human pathophysiology. The pore-forming α-subunit KCNQ1, which belongs to the voltage-gated ion channel superfamily, associates to its β-auxiliary subunit KCNE1 to generate the slow cardiac potassium IKs current, whose dysfunction leads to cardiac arrhythmia. Using pharmacology, gene invalidation, and single-molecule fluorescence assays, we found that KCNE1 fulfils all criteria of a bona fide auxiliary subunit of the TMEM16A chloride channel, which belongs to the anoctamin superfamily. Strikingly, assembly with KCNE1 switches TMEM16A from a calcium-dependent to a voltage-dependent ion channel. Importantly, clinically relevant inherited mutations within the TMEM16A-regulating domain of KCNE1 abolish the TMEM16A modulation, suggesting that the TMEM16A-KCNE1 current may contribute to inherited pathologies. Altogether, these findings challenge the dogma of the specificity of auxiliary subunits regarding protein complexes and questions ion channel classification.

Pipeline for the identification and classification of ion channels in parasitic flatworms.

BackgroundIon channels are well characterised in model organisms, principally because of the availability of functional genomic tools and datasets for these species. This contrasts the situation, for example, for parasites of humans and animals, whose genomic and biological uniqueness means that many genes and their products cannot be annotated. As ion channels are recognised as important drug targets in mammals, the accurate identification and classification of parasite channels could provide major prospects for defining unique targets for designing novel and specific anti-parasite therapies. Here, we established a reliable bioinformatic pipeline for the identification and classification of ion channels encoded in the genome of the cancer-causing liver fluke Opisthorchis viverrini, and extended its application to related flatworms affecting humans.MethodsWe built an ion channel identification + classification pipeline (called MuSICC), employing an optimised support vector machine (SVM) model and using the Kyoto Encyclopaedia of Genes and Genomes (KEGG) classification system. Ion channel proteins were first identified and grouped according to amino acid sequence similarity to classified ion channels and the presence and number of ion channel-like conserved and transmembrane domains. Predicted ion channels were then classified to sub-family using a SVM model, trained using ion channel features.ResultsFollowing an evaluation of this pipeline (MuSICC), which demonstrated a classification sensitivity of 95.2 % and accuracy of 70.5 % for known ion channels, we applied it to effectively identify and classify ion channels in selected parasitic flatworms.ConclusionsMuSICC provides a practical and effective tool for the identification and classification of ion channels of parasitic flatworms, and should be applicable to a broad range of organisms that are evolutionarily distant from taxa whose ion channels are functionally characterised.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1428-2) contains supplementary material, which is available to authorized users.

Techniques for recording reconstituted ion channels

This review describes and discusses techniques useful for monitoring the activity of protein ion channels in vitro. In the first section the biological importance and the classification of ion channels are outlined in order to justify the strong motivation for dealing with this important class of membrane proteins. The expression, reconstitution and integration of recombinant proteins into lipid bilayers are crucial steps to obtain consistent data when working with ion channels. In the second section recording techniques used in research are presented. Since this review focuses on analytical systems bearing reconstituted ion channels the industrial most important patch-clamp techniques of cells are only briefly mentioned. In section three, artificial systems developed in the last decades are described while the emerging technologies using nanostructured supports or microfluidic systems are presented in section four. Finally, the remaining challenges of membrane protein analysis and its potential applications are briefly outlined.

Physiologic Principles Underlying Ion Channelopathies

The ion channelopathies are a diverse array of human disorders caused by mutations in genes coding for ion channels. More than 40 different channelopathies have been identified, with representative disorders from every major class of ion channel and affecting all electrically excitable tissues: brain, peripheral nerve, skeletal muscle, smooth muscle, and heart. This review provides an overview of ion channel classification, structure, and function as a framework for understanding which ion channel properties are altered by disease-associated mutations and how these changes disrupt cellular excitability for channelopathies affecting skeletal muscle and the CNS.

Classification of ion channels in the luminal and abluminal membranes of guinea‐pig endocardial endothelial cells.

1. The ion channels on both the luminal and abluminal membranes of endocardial endothelial (EE) cells were separately recorded using the patch clamp technique in the guinea-pig heart. 2. The major population consisted of two types of non-selective cation channels, which showed open probabilities of 0.21 and 0.33 at the resting potential, and conductances of 36 and 11 pS, respectively. 3. The next major class was Cl- channels with an ohmic conductance of 409 pS. The channel was quiescent in the cell-attached mode but was activated by strong depolarization after excising the patch membrane. 4. The channels activated by intracellular Ca2+ were mainly K+ channels showing a 34 pS slope conductance and, less frequently, Ca(2+)-dependent K+ channels having a large conductance (210 pS). The inward rectifier K+ channel (32 pS) was also observed. 5. The non-selective cation channels were recorded on the luminal membrane, but scarcely on the abluminal membrane, suggesting an active transport of K+ and Na+ across the endocardium. 6. The resting membrane conductance of the EE cells may be provided mostly by non-selective cation channels and 34 pS Ca(2+)-dependent K+ channels.

Nonselective cation channels.

“Assuming that acetylcholine produces a large non-selective increase of ion permeability, i.e. a short-circuit,...” wrote Fatt and Katz in 1951. That was a year before Hodgkin and Huxley (1952) published their pioneering papers in which they suggested selective changes of nerve membrane permeability for Na+-ions and K+-ions as an explanation for the characteristic shape of action potentials. Selectivity for different ions is an important criterion for classification of ion channels. We can now state that acetylcholine-sensitive ion channels are indeed nonselective for monovalent cations, and that there are even many more types of ion channels characterized by different degrees of nonselectivity. With this book the authors try to demonstrate the current state of research in this field.