Constitutive Activity of Ionotropic Glutamate Receptors Explained

Belangrijkste concepten

A conserved aspartate residue controls ligand potency and channel activity in ionotropic glutamate receptors, leading to constitutive activation in certain subunits.

Samenvatting

Neurotransmitter ligands activate ionotropic glutamate receptor (iGluR) ion channels by binding to the ligand-binding domain (LBD), triggering channel opening. The conserved aspartate residue D732 plays a crucial role in controlling ligand potency and channel activity. Mutations at this position can lead to NMDA receptors that are solely activated by glutamate, bypassing the need for glycine. A homomeric iGluR from Trichoplax adhaerens has evolved into a leak channel due to native mutations at this residue, inhibited by neurotransmitter binding. The D732L and D732F substitutions in GluN1 subunits yield NMDA receptors activated solely by glutamate, with no dependence on glycine. These mutations render GluN1 subunits constitutively active, suggesting a dominant contribution of this residue to both ligand recognition and channel activity across different iGluRs.

Statistieken

Glycine potency decreased 1,000-10,000-fold with small side chain substitutions at D732.
Large currents were activated by 100 nM glycine/100 µM glutamate in GluN1-D732L/GluN2A-WT receptors.
Glutamate alone elicited concentration-dependent currents in GluN1-D732L/GluN2A-WT and GluN1-D732F/GluN2A-WT receptors.
DCKA inhibition was drastically increased in mutant receptors relative to WT receptors.
Q536 and D732 are energetically coupled residues affecting receptor activation.

Citaten

"Mutations at the conserved aspartate residue control both ligand potency and channel activity."
"A homomeric iGluR from Trichoplax adhaerens has evolved into a leak channel due to native mutations at this crucial residue."
"The D732L and D732F substitutions yield NMDA receptors activated solely by glutamate."

Belangrijkste Inzichten Gedestilleerd Uit

Constitutive activity of ionotropic glutamate receptors via hydrophobic substitutions in the ligand-binding domain

by Seljeset,S.,... om www.biorxiv.org 08-06-2023

https://www.biorxiv.org/content/10.1101/2023.08.03.551817v2

Diepere vragen

How might the findings regarding the conserved aspartate residue impact drug development targeting ionotropic glutamate receptors?

The discovery of the conserved aspartate residue's crucial role in controlling ligand potency and channel activity in ionotropic glutamate receptors (iGluRs) has significant implications for drug development targeting these receptors. Understanding how mutations at this specific residue can lead to constitutive activation or altered ligand sensitivity provides valuable insights into designing drugs that modulate iGluR function. By targeting this conserved residue, researchers could potentially develop novel compounds that selectively activate or inhibit iGluRs with high specificity, offering new therapeutic avenues for neurological disorders where iGluR dysfunction plays a role.

Could other amino acid residues within the ligand-binding domain play similar roles in controlling receptor activation?

While the focus of the study was on the conserved aspartate residue at position 732 (or equivalent) within the ligand-binding domain of ionotropic glutamate receptors, it is likely that other amino acid residues within this domain also play critical roles in controlling receptor activation. Given the complex interplay between different residues and their interactions during ligand binding and channel gating, it is plausible that additional amino acids contribute to determining receptor activity. Further research exploring the functional significance of other key residues within the ligand-binding domain may reveal similar mechanisms of control over receptor activation.

What implications do these results have for understanding the evolution of ionotropic glutamate receptor function?

The findings regarding the conserved aspartate residue and its impact on ionotropic glutamate receptor function provide valuable insights into understanding the evolutionary aspects of these receptors. The identification of a naturally occurring hydrophobic substitution at this critical position in Trichoplax adhaerens AKDF19383 highlights evolutionary adaptations that have led to unique channel properties in certain species. This suggests that changes in specific amino acids within iGluRs have played a significant role in shaping their functional diversity across different organisms over time. By studying how variations at key positions influence receptor activity, researchers can gain a deeper understanding of how iGluRs have evolved to fulfill distinct physiological roles throughout evolution.