Stargazin and cornichon-3 relieve polyamine block of AMPA receptors by enhancing blocker permeation.

Most ligand- and voltage-gated ion channels assemble as signaling complexes consisting of pore-forming and auxiliary subunits. In the mammalian brain, AMPA-type ionotropic glutamate receptors (AMP ARs) coassemble with several families of auxiliary subunits that regulate channel gating as well as ion channel block and permeation. Previous work has shown that auxiliary proteins stargazin (or gamma 2) and cornichon-3 (CNIH-3) attenuate the cytoplasmic polyamine channel block of AMP ARs, although the underlying mechanism has yet to be established. Here, we show that gamma 2 and CNIH-3 relieve channel block by enhancing the rate of blocker permeation. Surprisingly, the relative permeability of the polyamine spermine (Spm) through the pore of the AMP AR-gamma 2 or -CNIH-3 complexes is considerably more than AMP ARs expressed alone. Spm permeability is comparable to that of Na+ for the GluA2-gamma 2 complex and four times greater than Na+ with GluA2 + CNIH-3. A modified model of permeant channel block fully accounts for both the voltage- and time-dependent nature of Spm block. Estimates of block rate constants reveal that auxiliary subunits do not attenuate block by shifting the location of the block site within the membrane electric field, and they do not affect the blocker's ability to reach it. Instead, gamma 2 and CNIH-3 relieve channel block by facilitating the blocker's exit rates from the open channel. From a physiological perspective, the relief of channel block exerted by gamma 2 and CNIH-3 ensures that there is unfettered signaling by AMP ARs at gluta-matergic synapses. Moreover, the pronounced ability of AMP ARs to transport polyamines may have an unexpected role in regulating cellular polyamine levels.