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Related Concept Videos

GPCR Desensitization01:12

GPCR Desensitization

G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
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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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Glutamate is a fundamental neurotransmitter in the central nervous system, playing a vital role in neuronal communication and various cognitive processes. Glutamate stands as the principal excitatory neurotransmitter in the brain. Its presence is crucial for the communication between neurons, underpinning essential processes such as synaptic transmission, neuronal excitability, and plasticity. These functions are vital for higher-order cognitive processes, including learning and memory. The...
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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 include the...
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Nondepolarizing (Competitive) Neuromuscular Blockers: Mechanism of Action

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Tachyphylaxis is described as a rapid decrease in response to a drug after repeated or continuous administration of the same drug dose. It is a phenomenon where the body becomes less responsive to a particular substance or intervention over time, requiring higher doses or stronger interventions to achieve the same effect. It results from adaptive changes in the body's receptors, signaling pathways, or physiological processes that occur in response to prolonged exposure to a stimulus.
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A High-throughput Calcium-flux Assay to Study NMDA-receptors with Sensitivity to Glycine/D-serine and Glutamate
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Conformational restriction blocks glutamate receptor desensitization.

Matthew C Weston1, Peter Schuck, Alokesh Ghosal

  • 1Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.

Nature Structural & Molecular Biology
|November 23, 2006
PubMed
Summary

Researchers created non-desensitizing kainate receptors using disulfide cross-links. This reveals that dimer rearrangements, not just active conformation, drive receptor desensitization in glutamate receptors.

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Structural Biology

Background:

  • Desensitization is a common characteristic of ligand-gated ion channels, impacting their function.
  • Understanding the mechanisms of desensitization is crucial for comprehending neuronal signaling.

Purpose of the Study:

  • To engineer non-desensitizing kainate-subtype glutamate receptors.
  • To investigate the structural basis of desensitization in AMPA and kainate receptors.

Main Methods:

  • Utilized crystal structure of GluR2 L483Y mutant as a template.
  • Employed intermolecular disulfide cross-links to stabilize receptor conformations.
  • Performed crystallographic analysis and functional studies on engineered receptor mutants.

Main Results:

  • Successfully generated non-desensitizing GluR5, GluR6, and GluR7 receptors via cross-linking.
  • Identified that dimer rearrangements, not solely the active conformation, are necessary for desensitization.
  • Observed conserved active conformations between AMPA and kainate receptors.

Conclusions:

  • The ligand-binding core dimer is a key regulator of ion channel activity.
  • Subtle structural variations contribute to the distinct functional properties of glutamate receptors.
  • Desensitization in these receptors is mediated by dynamic dimer rearrangements.