R/G editing in GluA2Rflop modulates the functional difference between GluA1 flip and flop variants in GluA1/2R heteromeric channels

Abstract

In α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors, RNA editing and alternative splicing generate sequence variants, and those variants, as in GluA2-4 AMPA receptor subunits, generally show different properties. Yet, earlier studies have shown that the alternatively spliced, flip and flop variants of GluA1 AMPA receptor subunit exhibit no functional difference in homomeric channel form. Using a laser-pulse photolysis technique, combined with whole-cell recording, we measured the rate of channel opening, among other kinetic properties, for a series of AMPA channels with different arginine/glycine (R/G) editing and flip/flop status. We find that R/G editing in the GluA2 subunit modulates the channel properties in both homomeric (GluA2Q) and complex (GluA2Q/2R and GluA1/2R) channel forms. However, R/G editing is only effective in flop channels. Specifically, editing at the R/G site on the GluA2R flop isoform accelerates the rate of channel opening and desensitization for GluA1/2R channels more pronouncedly with the GluA1 being in the flop form than in the flip form; yet R/G editing has no effect on either channel-closing rate or EC50. Our results suggest R/G editing via GluA2R serve as a regulatory mechanism to modulate the function of GluA2R-containing, native receptors involved in fast excitatory synaptic transmission.

Stargazin and γ4 slow the channel opening and closing rates of GluA4 AMPA receptors

“…This assumption was consistent with our observation that the whole-cell current rise followed a first-order rate law (Eq. 2) in the entire range of glutamate concentrations not only in this study but also in all of our previous studies of other AMPA receptors 29,30,48–53 .…”

Adenosine‐to‐Inosine RNA Editing in Mouse and Human Brain Proteomes

“…For them, both flip and flop splice isoforms with R/G editing were identified (Table ). It was recently shown that this type of editing accelerated opening and desensitization of GRIA2‐formed ion channels, at least for flop isoforms . The better recognized Q/R editing site on GRIA2, which was shown to be completely edited in adult brains, was also identified with lesser spectral counts than the R/G site, most likely due to the chemical properties of the corresponding peptide.…”

“…For proteins, the main instrument was to create recombinant, forcibly edited receptors in cell and organism models. With targeted proteomics based on our findings, one can monitor dynamics of the edited isoform in intact tissues, including clinical samples …”

Proteome-Wide Analysis of ADAR-Mediated Messenger RNA Editing during Fruit Fly Ontogeny

“…Editing of this site is extensively growing at each phase of life cycle, presumably illustrating its functional importance. This type of substitution from RNA editing changes the size and electrostatic charge of a residue and was shown to modulate their electrophysiological properties for rat glutamate channel subunits [52].…”