Lysine 445 is a molecular indicator of subunit‐specific AMPA receptor binding domains

Despite strong homology between subunits of AMPA-type glutamate receptors, heteromeric assemblies in different brain regions vary in subunit composition and functional properties. We have previously shown that charge substitution at K445 decreases the apparent potency of AMPA for GluR-A receptors, although an analogous mutation is a low conductance B subunit of AB heteromers did not diminish AMPA potency. To examine the subunit selectivity of K445, we now measure the apparent potency of AMPA and glutamate at recombinant homomeric receptors containing the high-conductance, unedited (586Q) GluR-B subunit (GluR-B(Q)) using two-electrode voltage-clamp. We find the decrease in apparent potency of AMPA is recapitulated for homomeric GluR-B(Q)K449E receptors, and is rescued by coexpression with wild-type GluR-A. These data are consistent with the hypothesis that AMPAR subunit composition is critical to agonist-dependent receptor activation, and suggest that GluR-A plays a dominant role in mediating receptor activation by AMPA.