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Related Concept Videos

Ion Channels01:19

Ion Channels

91.6K
The movement of ions like sodium, potassium, and calcium into and out of the cell is essential to maintain the electrochemical gradient in living cells. The ion channels—a class of membrane transport proteins—help maintain this ionic gradient for the smooth functioning of physiological activities such as maintaining cell size and volume, conducting nerve impulses, and gas and nutrient exchange.
Ion channels are specialized integral membrane proteins on the plasma membrane that allow...
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Non-gated Ion Channels01:24

Non-gated Ion Channels

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Ion channels are specialized proteins on the plasma membrane that allow charged ions to pass down their electrochemical gradient. Their main function is to maintain the membrane potential which is critical for cell viability. These channels are either gated or non-gated and can transport more than a thousand ions within milliseconds for the cellular event to occur.
Compared to the gated ion channels, the non-gated channels, also known as leakage or passive channels, have no gating mechanism....
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Mechanically-gated Ion Channels01:12

Mechanically-gated Ion Channels

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Mechanically-gated ion channels are proteins found in eukaryotic and prokaryotic cell membranes that open in response to mechanical stress. Tension, compression, swelling, and shear stress can alter the conformation of the protein, opening a transmembrane channel that allows the passage of ions for signal transmission. In eukaryotes, mechanically-gated channels are distributed in several regions like the neurons, lungs, skin, bladder, and heart, where they play critical roles in numerous...
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Ligand-gated Ion Channels01:19

Ligand-gated Ion Channels

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Ligand-gated ion channels are transmembrane proteins with a channel for ions to pass through and a binding site for a ligand. The channel opens only when a ligand attaches to the binding site.
Three Subfamilies of Ligand-gated Ion Channels
Ligand-gated ion channels fall into three subfamilies. The 'Cys-loop' includes the nicotinic acetylcholine receptors, γ-aminobutyric acid (GABA), glycine, and 5-hydroxytryptamine receptors. The second one is the 'Pore-loop' channels that...
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Voltage-gated Ion Channels01:26

Voltage-gated Ion Channels

11.1K
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 types of...
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G-Protein Gated Ion Channels01:21

G-Protein Gated Ion Channels

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GPCRs are primarily responsible for our sense of smell, taste, and vision.  The binding of a sensory stimulus activates GPCR to stimulate effector proteins, many of which are ion channels in the sensory organs. GPCRs modulate the opening and closing of the target ion channels either directly by binding them, or by releasing second messengers that activate these channels. As ions move across the membrane, the membrane potential is altered, which induces an appropriate response.
Sensory...
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Detection of Rare Genomic Variants from Pooled Sequencing Using SPLINTER
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Exploiting ion channel structure to assess rare variant pathogenicity.

Brett M Kroncke1, Tao Yang1, Prince Kannankeril2

  • 1Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Heart Rhythm
|January 14, 2018
PubMed
Summary

Two genetic variants in KCNQ1 and KCNH2 genes were evaluated for long QT syndrome. Structural analysis revealed one variant (KCNH2 Ser55Leu) is pathogenic, while the other (KCNQ1 Val162Met) is benign.

Keywords:
Inherited arrhythmiasKCNH2KCNQ1Long QTProtein structure

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Area of Science:

  • Cardiovascular genetics
  • Molecular biology
  • Structural biology

Background:

  • A patient with long QT syndrome was identified as a carrier for two variants: KCNQ1 Val162Met and KCNH2 Ser55Leu.
  • Both variants were initially classified as pathogenic by a diagnostic laboratory, partly due to their sequence proximity to known pathogenic variants.

Observation:

  • The study employed co-segregation analysis within a family, in vitro electrophysiology using patch clamp techniques, and structural analysis utilizing cryo-electron microscopy data.
  • KCNQ1 Val162Met was found to be positioned away from critical functional regions in the protein structure.
  • KCNH2 Ser55Leu was located in a domain crucial for the fast inactivation of the KCNH2 channel.

Findings:

  • Structural analysis indicated KCNQ1 Val162Met is likely benign, whereas KCNH2 Ser55Leu is pathogenic.
  • Clinical phenotyping and electrophysiology studies corroborated these findings, confirming KCNH2 Ser55Leu as pathogenic and KCNQ1 Val162Met as benign.

Implications:

  • Sequence proximity alone is not a reliable indicator of variant pathogenicity.
  • Integrating advanced structural methods, such as cryo-electron microscopy, can significantly enhance the accuracy of variant pathogenicity prediction in genetic diagnostics.