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Related Concept Videos

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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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.
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Voltage-gated Ion Channels01:26

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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.
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Non-gated Ion Channels01:24

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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.
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G-Protein Gated Ion Channels01:21

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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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Tight Junctions01:29

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TMEM63 proteins function as monomeric high-threshold mechanosensitive ion channels.

Wang Zheng1, Shaun Rawson2, Zhangfei Shen3

  • 1Departments of Otolaryngology & Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.

Neuron
|August 5, 2023
PubMed
Summary

Mechanically activated ion channels TMEM63s unexpectedly function as monomers, unlike related OSCAs. This monomeric form and variations in the IL2 linker influence their high-threshold mechanosensitivity.

Keywords:
IL2OSCATM6TMCTMEM16TMEM63high-thresholdion channelmechanosensitiveoligomerization

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Area of Science:

  • Molecular and Cellular Biology
  • Biophysics
  • Structural Biology

Background:

  • OSCA and TMEM63 proteins are known mechanically activated (MA) ion channels involved in cellular mechanotransduction.
  • Typically, OSCAs, TMEM16, and TMC proteins form homodimers with dual pores, suggesting oligomerization is crucial for their function.
  • The structural basis and functional implications of TMEM63 proteins, particularly their oligomeric state, remain incompletely understood.

Purpose of the Study:

  • To investigate the oligomeric state and structural characteristics of TMEM63 proteins (TMEM63A and TMEM63B).
  • To determine the functional properties, including conductance and activation thresholds, of TMEM63 ion channels.
  • To explore the role of the intracellular linker IL2 and its evolutionary variations in OSCA/TMEM63 channel gating and oligomerization.

Main Methods:

  • X-ray crystallography was employed to determine the high-resolution structures of TMEM63A and TMEM63B.
  • Electrophysiological recordings (e.g., patch-clamp) were used to analyze the mechanosensitive currents of TMEM63s and engineered OSCA1.2 channels.
  • Site-directed mutagenesis was performed to investigate the function of the IL2 linker and specific residues in channel gating and oligomerization.

Main Results:

  • TMEM63A and TMEM63B were found to exist in a monomeric configuration, featuring a single, highly restricted ion pore.
  • Functional analysis confirmed TMEM63s as bona fide mechanosensitive ion channels with small conductance and high activation thresholds.
  • Modifications to the IL2 linker, including replacement with OSCA1.2 IL2 or mutations, resulted in monomeric OSCA1.2 channels and elevated MA current thresholds.

Conclusions:

  • TMEM63 proteins represent a unique class of monomeric mechanosensitive ion channels, distinct from dimeric OSCAs.
  • The intracellular linker IL2 and its structural variations play a critical role in modulating channel oligomerization and mechanosensitivity thresholds.
  • These findings suggest conserved and divergent gating mechanisms across the OSCA/TMEM63, TMEM16, and TMC channel families.