Figure 7. Schematic model for the function of site-G.

Transport of Ca²⁺ through the AMPAR pore requires both Site-G and the Q/R site. Site-G is at the channel gate outside the membrane electric field, while the Q/R site of the selectivity filter sits within the membrane electric field. (left) When Ca²⁺ binds to site-G it partially prevents the passage of Na⁺, causing external Ca²⁺ block of currents carried by Na⁺. Due to this arrangement, Ca²⁺ entry to the Q/R site is maintained even though physiological external Ca²⁺ concentration is about 50-fold lower than Na⁺. This distinction accounts for the efficient divalent permeability in GluA2-iQ (A2(Q)) channels. (middle) In GluA2-iR (A2(R)), Ca²⁺ can still access site-G but cannot permeate beyond the Q/R site. External Ca²⁺ block is present, and voltage-independent, consistent with site-G being located outside the membrane electric field. (right) For GluA2-iQ N619K mutant channels (N-K mutant), site-G can no longer bind Ca²⁺, and thus external Ca²⁺ block is weak. Attenuated site-G reduces the ability of Ca²⁺ to reach the Q/R site, ultimately leading to lower Ca²⁺ permeability.