Ivica, J. | bioRxiv Science

bioRxiv2026

Structural basis for GluA1 AMPA receptor regulation by PRRT1/SynDIG4 in LTP

AMPA receptor (AMPAR) signalling underlies long-term potentiation (LTP), a cellular mechanism for learning that selectively involves GluA1-type AMPARs through incompletely understood mechanisms. Here, we report a key role for the auxiliary subunit PRRT1/SynDIG4 in LTP. Cryo-EM structures of hippocampal AMPARs reveal preferential association of PRRT1 with GluA1 via its membrane-embedded CD225 domain, which sequesters the GluA1 C-terminus through a previously unexplored lipid modification on Cys825. Consequently, GluA1 regulatory motifs implicated in LTP, including the CaMKII binding site, are inaccessible. PRRT1 overexpression impairs LTP, which is rescued by the Cys825Ser mutation, presumably by restoring access of the GluA1 tail to Ser831 phosphorylation by CaMKII. Our data uncover a mechanism wherein PRRT1/SynDIG4 controls the availability of the GluA1 pool that is released upon the induction of LTP.

neuroscience↗

bioRxiv2022

Aminomethanesulfonic acid illuminates the boundary between full and partial agonists of the pentameric glycine receptor

To clarify the determinants of agonist efficacy in pentameric ligand-gated ion channels we examined a new compound, aminomethanesulfonic acid (AMS), a molecule intermediate in structure between glycine and taurine. Despite wide availability, to date there are no reports of AMS action on glycine receptors, perhaps because AMS is unstable at physiological pH. Here we show that at pH 5, AMS is an efficacious agonist, eliciting in zebrafish 1 glycine receptors a maximum single channel open probability of 0.85, much greater than that of {beta}-alanine (0.54) or taurine (0.12), and second only to that of glycine itself (0.96). Thermodynamic cycle analysis of the efficacy of these closely related agonists shows supra-additive interaction between changes in the length of the agonist molecule and the size of the anionic moiety. Single particle cryo-EM structures of AMS-bound glycine receptors show that the AMS-bound agonist pocket is as compact as with glycine, and three-dimensional classification demonstrates that the channel populates the open and the desensitized states, like glycine, but not the closed intermediate state associated with the weaker partial agonists, {beta}-alanine and taurine. Because AMS is on the cusp between full and partial agonists, it provides a new tool to help us understand agonist action in the pentameric superfamily of ligand-gated ion channels.

biophysics↗