Partial Agonism in Heteromeric GLUK2/GLUK5 Kainate Receptor

Authors

Nabina Paudyal
Anindita Das
Elisa Carrillo
Vladimir Berka
Vasanthi Jayaraman

Publication Date

1-1-2025

Journal

Proteins

DOI

10.1002/prot.26565

PMID

37526035

PMCID

PMC10830895

PubMedCentral® Posted Date

7-1-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Kainate receptors are a subtype of ionotropic glutamate receptors that form transmembrane channels upon binding glutamate. Here, we have investigated the mechanism of partial agonism in heteromeric GluK2/K5 receptors, where the GluK2 and GluK5 subunits have distinct agonist binding profiles. Using single-molecule Förster resonance energy transfer, we found that at the bi-lobed agonist-binding domain, the partial agonist AMPA-bound receptor occupied intermediate cleft closure conformational states at the GluK2 cleft, compared to the more open cleft conformations in apo form and more closed cleft conformations in the full agonist glutamate-bound form. In contrast, there is no significant difference in cleft closure states at the GluK5 agonist-binding domain between the partial agonist AMPA- and full agonist glutamate-bound states. Additionally, unlike the glutamate-bound state, the dimer interface at the agonist-binding domain is not decoupled in the AMPA-bound state. Our findings suggest that partial agonism observed with AMPA binding is mediated primarily due to differences in the GluK2 subunit, highlighting the distinct contributions of the subunits towards activation.

Keywords

Receptors, Kainic Acid, GluK2 Kainate Receptor, Humans, Protein Multimerization, Glutamic Acid, Protein Binding, Fluorescence Resonance Energy Transfer, Binding Sites, Models, Molecular, alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, HEK293 Cells, Animals, Protein Domains, agonist AMPA, conformational dynamics, heteromeric GluK2/GluK5, partial agonism, smFRET

Published Open-Access

yes

Recommended Citation

Paudyal, Nabina; Das, Anindita; Carrillo, Elisa; et al., "Partial Agonism in Heteromeric GLUK2/GLUK5 Kainate Receptor" (2025). Faculty, Staff and Student Publications. 4532.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4532