scholarly journals Predicting the functional effects of voltage-gated potassium channel missense variants with multi-task learning

2021 ◽  
Author(s):  
Christian Malte Boßelmann ◽  
Ulrike B.S. Hedrich ◽  
Peter Müller ◽  
Lukas Sonnenberg ◽  
Shridhar Parthasarathy ◽  
...  
Keyword(s):  
Potassium Channels ◽  
Ion Channel ◽  
Neurological Diseases ◽  
Predictive Performance ◽  
Support Vector ◽  
Loss Of Function ◽  
Functional Changes ◽  
Voltage Gated ◽  
Task Learning ◽  
Number Of Patients

AbstractPurposeVariants in genes encoding voltage-gated potassium channels are associated with a broad spectrum of neurological diseases including epilepsy, ataxia, and intellectual disability. Knowledge of the resulting functional changes, characterized as overall ion channel gain- or loss-of-function, is essential to guide clinical management including precision medicine therapies. However, for an increasing number of variants, little to no experimental data is available. New tools are needed to evaluate variant functional effects.MethodsWe catalogued a comprehensive dataset of 959 functional experiments across 19 voltage-gated potassium channels, leveraging data from 782 unique disease-associated and synthetic variants. We used these data to train a taxonomy-based multi-task learning support vector machine (MTL-SVM), and compared performance to a baseline of standard SVMs.ResultsMTL-SVM maintains channel family structure during model training, improving overall predictive performance (mean balanced accuracy 0.729 ± 0.029, AU-ROC 0.757 ± 0.039) over baseline (mean balanced accuracy 0.645 ± 0.041, AU-ROC 0.710 ± 0.074). We can obtain meaningful predictions even for channels with few known variants (KCNC1, KCNQ5).ConclusionOur model enables functional variant prediction for voltage-gated potassium channels. It may assist in tailoring current and future precision therapies for the increasing number of patients with ion channel disorders.

scholarly journals Panama: A tool for ion channel biophysics simulation

2018 ◽  
Author(s):  
Anuj Guruacharya
Keyword(s):  
Ion Channels ◽  
Potassium Channels ◽  
Calcium Channels ◽  
Ion Channel ◽  
Chloride Channels ◽  
High Threshold ◽  
Spreadsheet Program ◽  
Online Tool ◽  
Voltage Gated ◽  
Web App

I have created an online tool and an R library that simulates biophysics of voltage-gated ion channels. It is made publicly available as an R library called Panama at github.com/anuj2054/panama and as a web app at neuronsimulator.com. A need for such a tool was observed after surveying available software packages. I found that the available packages are either not robust enough to simulate multiple ion channels, too complicated, usable only as desktop software, not optimized for mobile devices, not interactive, lacking intuitive graphical controls, or not appropriate for undergraduate education. My app simulates the physiology of 11 different channels - voltage-gated sodium, potassium, and chloride channels; channels causing A-current, M-current, and After-HyperPolarization (AHP) current; calcium-activated potassium channels; low threshold T type calcium channels and high threshold L type calcium channels; leak sodium and leak potassium channels. It can simulate these channels under both current clamp and voltage clamp conditions. As we change the input values on the app, the output can be instantaneously visualized on the web browser and downloaded as a data table to be further analyzed in a spreadsheet program. The app is a first of its kind, mobile-friendly and touch-screen-friendly online tool that can be used to teach undergraduate neuroscience classes. It can also be used by researchers on their local computers as part of an R library. It has intuitive touch-optimized controls, instantaneous graphical output, and yet is pedagogically robust for education and casual research purposes.Neuroscience education, ion channel biophysics, Hodgkin-Huxley simulation, web app for neuroscience

scholarly journals Consensus channelome of dinoflagellates revealed by transcriptomic analysis sheds light on their physiology

ALGAE ◽  
2021 ◽  
Vol 36 (4) ◽  
pp. 315-326
Author(s):  
Ilya Pozdnyakov ◽  
Olga Matantseva ◽  
Sergei Skarlato
Keyword(s):  
Ion Channels ◽  
Potassium Channels ◽  
Ion Channel ◽  
Chloride Channels ◽  
Cation Channels ◽  
Mechanosensitive Channels ◽  
Anion Channels ◽  
Voltage Gated ◽  
Calcium Activated Potassium Channels ◽  
Pore Domain

Ion channels are membrane protein complexes mediating passive ion flux across the cell membranes. Every organism has a certain set of ion channels that define its physiology. Dinoflagellates are ecologically important microorganisms characterized by effective physiological adaptability, which backs up their massive proliferations that often result in harmful blooms (red tides). In this study, we used a bioinformatics approach to identify homologs of known ion channels that belong to 36 ion channel families. We demonstrated that the versatility of the dinoflagellate physiology is underpinned by a high diversity of ion channels including homologs of animal and plant proteins, as well as channels unique to protists. The analysis of 27 transcriptomes allowed reconstructing a consensus ion channel repertoire (channelome) of dinoflagellates including the members of 31 ion channel families: inwardly-rectifying potassium channels, two-pore domain potassium channels, voltage-gated potassium channels (Kv), tandem Kv, cyclic nucleotide-binding domain-containing channels (CNBD), tandem CNBD, eukaryotic ionotropic glutamate receptors, large-conductance calcium-activated potassium channels, intermediate/small-conductance calcium-activated potassium channels, eukaryotic single-domain voltage-gated cation channels, transient receptor potential channels, two-pore domain calcium channels, four-domain voltage-gated cation channels, cation and anion Cys-loop receptors, small-conductivity mechanosensitive channels, large-conductivity mechanosensitive channels, voltage-gated proton channels, inositole-1,4,5- trisphosphate receptors, slow anion channels, aluminum-activated malate transporters and quick anion channels, mitochondrial calcium uniporters, voltage-dependent anion channels, vesicular chloride channels, ionotropic purinergic receptors, animal volage-insensitive cation channels, channelrhodopsins, bestrophins, voltage-gated chloride channels H+/Cl- exchangers, plant calcium-permeable mechanosensitive channels, and trimeric intracellular cation channels. Overall, dinoflagellates represent cells able to respond to physical and chemical stimuli utilizing a wide range of Gprotein coupled receptors- and Ca2+-dependent signaling pathways. The applied approach not only shed light on the ion channel set in dinoflagellates, but also provided the information on possible molecular mechanisms underlying vital cellular processes dependent on the ion transport.

scholarly journals Local Sequence Information-based Support Vector Machine to Classify Voltage-gated Potassium Channels

2006 ◽  
Vol 38 (6) ◽  
pp. 363-371 ◽  
Author(s):  
Li-Xia LIU ◽  
Meng-Long LI ◽  
Fu-Yuan TAN ◽  
Min-Chun LU ◽  
Ke-Long WANG ◽  
...  
Keyword(s):  
Support Vector Machine ◽  
Potassium Channels ◽  
Support Vector ◽  
Sequence Information ◽  
Voltage Gated ◽  
Local Sequence

scholarly journals Voltage-Gated Ca2+-Channel α1-Subunit de novo Missense Mutations: Gain or Loss of Function – Implications for Potential Therapies

2021 ◽  
Vol 13 ◽  
Author(s):  
Jörg Striessnig
Keyword(s):  
De Novo ◽  
Current Knowledge ◽  
Autism Spectrum ◽  
Special Focus ◽  
Endocrine Disorders ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Functional Changes ◽  
Voltage Sensors ◽  
Voltage Gated

This review summarizes our current knowledge of human disease-relevant genetic variants within the family of voltage gated Ca2+ channels. Ca2+ channelopathies cover a wide spectrum of diseases including epilepsies, autism spectrum disorders, intellectual disabilities, developmental delay, cerebellar ataxias and degeneration, severe cardiac arrhythmias, sudden cardiac death, eye disease and endocrine disorders such as congential hyperinsulinism and hyperaldosteronism. A special focus will be on the rapidly increasing number of de novo missense mutations identified in the pore-forming α1-subunits with next generation sequencing studies of well-defined patient cohorts. In contrast to likely gene disrupting mutations these can not only cause a channel loss-of-function but can also induce typical functional changes permitting enhanced channel activity and Ca2+ signaling. Such gain-of-function mutations could represent therapeutic targets for mutation-specific therapy of Ca2+-channelopathies with existing or novel Ca2+-channel inhibitors. Moreover, many pathogenic mutations affect positive charges in the voltage sensors with the potential to form gating-pore currents through voltage sensors. If confirmed in functional studies, specific blockers of gating-pore currents could also be of therapeutic interest.

scholarly journals PSIONplusm Server for Accurate Multi-Label Prediction of Ion Channels and Their Types

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 876
Author(s):  
Jianzhao Gao ◽  
Hong Wei ◽  
Alberto Cano ◽  
Lukasz Kurgan
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Computational Prediction ◽  
Support Vector ◽  
Multiple Channel ◽  
Voltage Gated ◽  
Prediction Mode ◽  
Label Prediction ◽  
Voltage Gated Channels ◽  
Empirical Tests

Computational prediction of ion channels facilitates the identification of putative ion channels from protein sequences. Several predictors of ion channels and their types were developed in the last quindecennial. While they offer reasonably accurate predictions, they also suffer a few shortcomings including lack of availability, parallel prediction mode, single-label prediction (inability to predict multiple channel subtypes), and incomplete scope (inability to predict subtypes of the voltage-gated channels). We developed a first-of-its-kind PSIONplusm method that performs sequential multi-label prediction of ion channels and their subtypes for both voltage-gated and ligand-gated channels. PSIONplusm sequentially combines the outputs produced by three support vector machine-based models from the PSIONplus predictor and is available as a webserver. Empirical tests show that PSIONplusm outperforms current methods for the multi-label prediction of the ion channel subtypes. This includes the existing single-label methods that are available to the users, a naïve multi-label predictor that combines results produced by multiple single-label methods, and methods that make predictions based on sequence alignment and domain annotations. We also found that the current methods (including PSIONplusm) fail to accurately predict a few of the least frequently occurring ion channel subtypes. Thus, new predictors should be developed when a larger quantity of annotated ion channels will be available to train predictive models.

Ion Channel Remodelling in Atrial Fibrillation

2011 ◽  
Vol 7 (2) ◽  
pp. 97 ◽  
Author(s):  
Niels Voigt ◽  
Dobromir Dobrev ◽  
◽  
Keyword(s):  
Atrial Fibrillation ◽  
Ion Channel ◽  
Antiarrhythmic Drugs ◽  
Current Knowledge ◽  
Bleeding Complications ◽  
Large Size ◽  
Cardiovascular Morbidity And Mortality ◽  
Number Of Patients ◽  
Life Threatening ◽  
Underlying Mechanisms

Atrial fibrillation (AF) is the most common arrhythmia and is associated with substantial cardiovascular morbidity and mortality, with stroke being the most critical complication. Present drugs used for the therapy of AF (antiarrhythmics and anticoagulants) have major limitations, including incomplete efficacy, risks of life-threatening proarrhythmic events and bleeding complications. Non-pharmacological ablation procedures are efficient and apparently safe, but the very large size of the patient population allows ablation treatment of only a small number of patients. These limitations largely result from limited knowledge about the underlying mechanisms of AF and there is a hope that a better understanding of the molecular basis of AF may lead to the discovery of safer and more effective therapeutic targets. This article reviews the current knowledge about AF-related ion-channel remodelling and discusses how these alterations might affect the efficacy of antiarrhythmic drugs.

Treponema, Iron and Neurodegeneration

2018 ◽  
Vol 15 (8) ◽  
pp. 716-722 ◽  
Author(s):  
A. Jolivet-Gougeon ◽  
M. Bonnaure-Mallet
Keyword(s):  
Iron Metabolism ◽  
Plasma Proteins ◽  
Iron Homeostasis ◽  
Neurological Diseases ◽  
Host Cells ◽  
Loss Of Function ◽  
Binding Ability ◽  
Iron Binding Proteins ◽  
Oxidative Species ◽  
Iron Reductase

Spirochetes are suspected to be linked to the genesis of neurological diseases, including neurosyphillis or neurodegeneration (ND). Impaired iron homeostasis has been implicated in loss of function in several enzymes requiring iron as a cofactor, formation of toxic oxidative species, inflammation and elevated production of beta-amyloid proteins. This review proposes to discuss the link that may exist between the involvement of Treponema spp. in the genesis or worsening of ND, and iron dyshomeostasis. Proteins secreted by Treponema can act directly on iron metabolism, with hemin binding ability (HbpA and HbpB) and iron reductase able to reduce the central ferric iron of hemin, iron-containing proteins (rubredoxin, neelaredoxin, desulfoferrodoxin metalloproteins, bacterioferritins etc). Treponema can also interact with cellular compounds, especially plasma proteins involved in iron metabolism, contributing to the virulence of the syphilis spirochetes (e.g. treponemal motility and survival). Fibronectin, transferrin and lactoferrin were also shown to be receptors for treponemal adherence to host cells and extracellular matrix. Association between Treponema and iron binding proteins results in iron accumulation and sequestration by Treponema from host macromolecules during systemic and mucosal infections.

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