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bioRxiv · 10.1101/2023.08.03.551817

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

Seljeset, S.·Sintsova, O.·Wang, Y.·Harb, H. Y.·Lynagh, T.
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Abstract

Neurotransmitter ligands electrically excite neurons by activating ionotropic glutamate receptor (iGluR) ion channels. Knowledge of the iGluR amino acid residues that dominate ligand-induced activation would enable the prediction of function from sequence. We therefore explored the molecular determinants of activity in rat NMDA-type iGluRs (NMDA receptors), complex heteromeric iGluRs comprising two glycine-binding GluN1 and two glutamate-binding GluN2 subunits, using amino acid sequence analysis, mutagenesis, and electrophysiology. We find that a broadly conserved aspartate residue controls both ligand potency and channel activity, to the extent that certain substitutions at this position bypass the need for ligand-binding in GluN1 subunits, generating NMDA receptors activated solely by glutamate. Furthermore, we identify a homomeric iGluR from the placozoan Trichoplax adhaerens that has utilized native mutations of this crucial residue to evolve into a leak channel that is inhibited by neurotransmitter binding, pointing to a dominant role of this residue throughout the iGluR superfamily.

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Seljeset, S., Sintsova, O., Wang, Y., Harb, H. Y., Lynagh, T.. 2023-08-06. Constitutive activity of ionotropic glutamate receptors via a hydrophobic plug in the ligand-binding domain. https://doi.org/10.1101/2023.08.03.551817

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