A Gate Hinge Controls the Epithelial Calcium Channel TRPV5.
Jenny van der Wijst1, Elizabeth H Leunissen1, Maxime G Blanchard1
1Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.
Scientific Reports
|April 5, 2017
Summary
Researchers identified a unique tryptophan (W583) in TRPV5 channels that controls calcium (Ca2+) permeation. Mutations in this residue enhance Ca2+ influx, leading to cell death and revealing a novel gating mechanism for calcium-selective channels.
Area of Science:
- Molecular Biology
- Biophysics
- Ion Channel Physiology
Background:
- Transient Receptor Potential Vanilloid 5 (TRPV5) channels are crucial for calcium homeostasis.
- TRPV5 exhibits high calcium selectivity and calcium-dependent inactivation, key features for its function.
- Understanding TRPV5 gating is essential for comprehending calcium transport mechanisms.
Purpose of the Study:
- To elucidate novel insights into TRPV5 channel gating mechanisms.
- To perform in-depth structure-function analysis of TRPV5.
- To identify molecular determinants of calcium permeation and inactivation.
Main Methods:
- Site-directed mutagenesis of TRPV5.
- Biochemical and electrophysiological analyses.
- Homology modeling of the TRPV5 channel structure.
Main Results:
- An exceptional tryptophan residue (W583) at the intracellular pore terminus was identified as unique to TRPV5/6.
- W583 was demonstrated to be a critical component of the calcium permeation gate.
- Mutations at W583 led to increased cell death via enhanced calcium influx, indicating altered channel function.
Conclusions:
- A novel channel gating mechanism involving W583 as a calcium permeation gate is proposed.
- Detailed molecular insights into the TRPV5 calcium permeation pathway were provided.
- The findings on W583's role may be extrapolated to other calcium-selective channels.
Related Concept Videos
01:24Non-gated Ion Channels
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.
Compared to the gated ion channels, the non-gated channels, also known as leakage or passive channels, have no gating mechanism.
01:12Mechanically-gated Ion Channels
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...
01:27Feedback Regulation of Calcium Concentration
Calcium is an essential signaling molecule required for various cellular functions. Calcium pumps and ion channels on cell and organellar membranes, such as those on the endoplasmic reticulum (ER), regulate calcium concentrations inside the cell. They remain closed, keeping the cytosolic calcium levels low at a resting state.
Various transmembrane receptors, such as G protein-coupled receptors (GPCRs), elicit a response to extracellular signals by increasing cytosolic calcium. Activated GPCRs...
Various transmembrane receptors, such as G protein-coupled receptors (GPCRs), elicit a response to extracellular signals by increasing cytosolic calcium. Activated GPCRs...
01:24Non-gated Ion Channels
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.
Compared to the gated ion channels, the non-gated channels, also known as leakage or passive channels, have no gating mechanism.
01:30Ligand-Gated Ion Channel Receptor: Gating Mechanism
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...
01:12Mechanically-gated Ion Channels
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...