Fig. 6.

Model accounting for the differential dependence of calcium permeability and inward rectification on GluR2 abundance. In the model two amino acid residues determine the major permeation properties: a ring of aspartates that are found in all AMPA subunits and are predicted by transmembrane topology to be located near the cytoplasmic mouth of the channel (Hollmann et al., 1994; Wo and Oswald, 1994; Bennett and Dingledine, 1995) and the Q/R site located four residues upstream (Hume et al., 1991; Burnashev et al., 1992). The essence of the model is that the ring of carbonyl oxygens in GluR2-lacking AMPA receptors (A) contributes to or forms a binding site for permeating divalent cations. Internal polyamines also interact with this ring of polar residues and, by electrostatic interactions of the positively charged amine groups, with the carboxyl groups of the ionized aspartates at D616. Incorporation of a single positively charged arginine into the Q/R site (B) disrupts the ring of carbonyl groups, which is postulated to eliminate the divalent ion binding site. This arginine also neutralizes a negative charge at the internal channel mouth by formation of a salt bridge between its guanidinium group and the carboxyl group of the aspartate, which reduces the number of anionic binding sites for internal polyamines and thus decreases their affinity for the channel. As more arginines are incorporated into the Q/R site (C), the number of negative charges at the channel mouth, and hence polyamine affinity for the internal blocking site, is progressively reduced.