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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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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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Ligand-Gated Ion Channel Receptor: Gating Mechanism01:30

Ligand-Gated Ion Channel Receptor: Gating Mechanism

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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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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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Drug Elimination by Renal Route: Tubular Secretion01:15

Drug Elimination by Renal Route: Tubular Secretion

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Once the process of glomerular filtration is completed, blood carrying unfiltered drug molecules traverses through efferent arterioles and makes its way into the peritubular capillaries in the proximal tubule. A variety of carriers play a pivotal role in actively secreting drugs from these peritubular capillaries into the tubular fluid. The organic anion transporter transfers acidic drugs, against an electrochemical gradient, from the peritubular capillaries into the renal tubule cells and...
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Pore Transport and Ion-Pair Transport01:17

Pore Transport and Ion-Pair Transport

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Pore transport and ion-pair formation are critical mechanisms for the absorption and distribution of drugs in the body.
Pore transport, also known as convective transport, is a process where small molecules like urea, water, and sugars rapidly cross cell membranes as though there were channels or pores in the membrane. Although direct microscopic evidence is limited  but the concept of pores or channels is widely accepted based on physiological evidence. Despite the lack of direct...
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Updated: May 27, 2025

Yeast Luminometric and Xenopus Oocyte Electrophysiological Examinations of the Molecular Mechanosensitivity of TRPV4
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Yeast Luminometric and Xenopus Oocyte Electrophysiological Examinations of the Molecular Mechanosensitivity of TRPV4

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Structural insights into TRPV2 modulation by probenecid.

Julia A Rocereta1,2, Toni Sturhahn3, Ruth A Pumroy1,2

  • 1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Nature Structural & Molecular Biology
|February 19, 2025
PubMed
Summary
This summary is machine-generated.

Probenecid (PBC) potentiates the TRPV2 channel by binding to a novel intracellular pocket, stabilizing an active conformation. This discovery offers new therapeutic strategies for cardiovascular conditions by targeting TRPV2 function.

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Cell-based Calcium Assay for Medium to High Throughput Screening of TRP Channel Functions using FlexStation 3
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Purification and Reconstitution of TRPV1 for Spectroscopic Analysis
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Purification and Reconstitution of TRPV1 for Spectroscopic Analysis

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Yeast Luminometric and Xenopus Oocyte Electrophysiological Examinations of the Molecular Mechanosensitivity of TRPV4
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Cell-based Calcium Assay for Medium to High Throughput Screening of TRP Channel Functions using FlexStation 3
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Purification and Reconstitution of TRPV1 for Spectroscopic Analysis
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Purification and Reconstitution of TRPV1 for Spectroscopic Analysis

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Area of Science:

  • Ion channel research
  • Cardiovascular physiology
  • Pharmacology

Background:

  • Transient receptor potential vanilloid 2 (TRPV2) channels are crucial in cardiovascular health and disease.
  • Probenecid (PBC), a uricosuric agent, has shown potential in improving cardiovascular function.

Purpose of the Study:

  • To investigate the mechanism by which Probenecid (PBC) interacts with and modulates the activity of the TRPV2 cation channel.
  • To elucidate the structural basis of PBC potentiation of TRPV2.

Main Methods:

  • Electrophysiology was used to measure TRPV2 channel activity.
  • Cryo-electron microscopy provided high-resolution structural data of PBC bound to TRPV2.
  • Site-directed mutagenesis was employed to investigate the role of specific amino acids.

Main Results:

  • Probenecid (PBC) significantly potentiates rat TRPV2 activity.
  • Cryo-EM revealed a novel intracellular binding pocket for PBC on TRPV2, involving a conserved histidine residue.
  • PBC binding prevents channel inactivation and can be extended to TRPV1 and TRPV3 channels via histidine substitution.
  • PBC in combination with 2-aminoethoxydiphenyl borate induces a potentiated TRPV2 state.

Conclusions:

  • Probenecid (PBC) directly binds to TRPV2 in a unique intracellular pocket, stabilizing a potentiated channel conformation.
  • This interaction mechanism provides a structural basis for TRPV2 modulation and suggests therapeutic potential for cardiovascular diseases.