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Related Concept Videos

Voltage-gated Ion Channels01:26

Voltage-gated Ion Channels

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Voltage-gated ion channels are transmembrane proteins that open and close in response to changes in the membrane potential. They are present on the membranes of all electrically excitable cells such as neurons, heart, and muscle cells.
Generally, all voltage-gated ion channels have a 'voltage-sensing domain' that spans the lipid bilayer. The charged residues in the sensor move in response to the membrane potential changes that open the channel allowing ions movement. There are several...
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Antiarrhythmic Drugs: Class I Agents as Sodium Channel Blockers01:22

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Class I antiarrhythmic drugs are used to treat various types of arrhythmias or irregular heart rhythms. These drugs block the sodium (Na+) channels in the cardiac cells, thereby affecting the movement of electrical impulses across the heart. Class I antiarrhythmic drugs are divided into three subgroups: Class IA, Class IB, and Class IC, each with distinct mechanisms of action and effects on the heart.
Class 1A Antiarrhythmic Drugs: These drugs work by moderately blocking sodium channels,...
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Antiepileptic Drugs: Sodium Channel Blockers01:08

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Antiepileptic drugs are specialized medications that prevent seizures in individuals diagnosed with epilepsy. These drugs primarily function by blocking the movement of sodium ions through channels in the neuronal membrane, inhibiting the repetitive firing of action potentials often associated with seizures.
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Antiepileptic Drugs: Modulators of Neurotransmitter Release Mediated by SV2A Protein01:20

Antiepileptic Drugs: Modulators of Neurotransmitter Release Mediated by SV2A Protein

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Antiepileptic drugs, such as levetiracetam (Keppra) and brivaracetam (Briviact), have emerged as crucial tools in managing epilepsy. These medications exert their therapeutic effects by targeting the synaptic vesicle protein SV2A, a transmembrane glycoprotein primarily found in the brain.
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Ligand-Gated Ion Channel Receptor: Gating Mechanism01:30

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Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
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Regulation of Sodium and Potassium01:26

Regulation of Sodium and Potassium

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The regulation of sodium and potassium ion concentrations in the human body is a complex process governed primarily by hormones such as aldosterone, antidiuretic hormone (ADH), and atrial natriuretic peptide (ANP).
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Identification and Classification of Position-specific GABAA Receptor Subunit Missense Variants for Their Role In Hippocampal Pyramidal Neurons
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Gene variant effects across sodium channelopathies predict function and guide precision therapy.

Andreas Brunklaus1,2, Tony Feng1,2, Tobias Brünger3

  • 1The Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK.

Brain : a Journal of Neurology
|January 17, 2022
PubMed
Summary

Similarities in voltage-gated sodium channel (SCN) gene variants predict function across different SCN genes. This finding aids in understanding channelopathies and guiding precision treatments for rare diseases.

Keywords:
SCN1ASCN2ASCN4ASCN5ASCN8A

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Area of Science:

  • Genetics and Molecular Biology
  • Neuroscience
  • Cardiology

Background:

  • Pathogenic variants in voltage-gated sodium channel (SCN) genes cause diverse disorders, including epilepsies, channelopathies, neuropathies, and arrhythmias.
  • Understanding the functional impact of these variants is crucial for developing targeted therapies, but experimental characterization is resource-intensive and limited.
  • The conserved nature of SCN genes suggests potential for cross-gene functional prediction.

Approach:

  • Conducted a systematic literature search to identify electrophysiologically characterized missense variants in SCN genes until April 2021.
  • Performed protein sequence alignments and correlated variant locations with functional effects (gain- or loss-of-function).
  • Analyzed variant data for 437 missense variants across nine SCN genes, focusing on epilepsy, neuromuscular, and cardiac phenotypes.

Key Points:

  • Identified 38 variant pairs with identical disease associations in different SCN genes, showing 92% agreement in functional consequences.
  • Pathogenic variants clustered in functional domains, while population variants were more frequent in non-conserved regions.
  • Pore-loop regions were linked to loss-of-function, inactivation sites to gain-of-function, and voltage-sensing regions to mixed effects.

Conclusions:

  • Biophysical characterization of variants in one SCN gene can predict function in other SCN genes lacking experimental data.
  • Developed the first gain- versus loss-of-function topological map of SCN proteins, revealing shared functional patterns.
  • Integrated findings into a free online webtool (http://SCN-viewer.broadinstitute.org) to aid variant interpretation and precision therapy.